Use of aerosolized levofloxacin for treating cystic fibrosis.
Abstract
La invención se refiere a métodos para tratar fibrosis quística que comprenden administrar a un humano que lo necesita una solución en aerosol que comprende levofloxacina u ofloxacina y un catión bivalente o trivalente. La invención se refiere en particular a la administración de la solución en aerosol a un humano en donde dicho humano tiene una infección pulmonar que comprende P. aeruginosa.

Term
3.9 yearsleft in the term
Expires 3 September 2030.
- Priority
- Filed
- Granted
- Today
- Expires
14 claims: 5 independent, 9 dependent
- 1REIVINDICACIONES 1. Un aerosol de una solución que comprende 75 mg/ml a 150 mg/ml de levofloxacino, 150 mM a 250 mM de un catión de magnesio y tiene un pH de 5 a 7 y una osmolalidad de 300 mOsmol/Kg a 500 mOsmol/kg, para uso en el tratamiento de una infección pulmonar de Pseudomonas aeruginosa en un paciente con fibrosis quistica;en donde la solución comprende 240 mg de levofloxacina y el aerosol está adaptado para ser administrable dos veces al día durante 28 dias.
- 2El aerosol para usarse de conformidad con la reivindicación 1, en donde la solución comprende 90 mg/ml a 110 mg/ml de levofloxacino y 175 mM a 225 mM de un catión de magnesio.
- 3El aerosol para usarse de conformidad con la reivindicación 1 o la reivindicación 2, en donde el catión de magnesio es cloruro de magnesio.
- 4El aerosol para usarse de conformidad con la reivindicación 3, en donde la solución comprende 100 mg/ml de levofloxacina y 200 mM de cloruro de magnesio, y tiene un pH de 6.2 y una osmolalidad de 383 mOsmol/kg.
- 5El aerosol para usarse de conformidad con la reivindicación 3, en donde la solución comprende 100 mg/ml de levofloxacina, 200 mM de magnesio y 400 mM de cloruro, y tiene una osmolalidad de 350 mOsmol/kg a 500 mOsmol/kg.
- 6El aerosol para usarse de conformidad con 128 5, IMPI MEXICANO en un ser humano cualquiera de las reivindicaciones 1 a está adaptado para ser administrable veces al día con un intervalo entre horas.
- 7El aerosol para usarse de conformidad con cualquiera de las reivindicaciones 1 a 6, en donde el aerosol está adaptado para ser administrable en un ser humano en menos de 10 minutos.
- 8El aerosol para usarse de conformidad con cualquiera de las reivindicaciones 1 a 7, en donde el aerosol está adaptado para ser administrable en un ser humano en menos de 5 minutos.
- 9El aerosol para usarse de conformidad con cualquiera de las reivindicaciones 1 a 8, en donde el aerosol tiene un diámetro aerodinámico medio en masa desde 2 micrómetros hasta 5 micrómetros con una desviación estándar geométrica menor o igual a 2.5 micrómetros.
- 10El aerosol para usarse de conformidad con cualquiera de las reivindicaciones 1 a 9, en donde el aerosol tiene un diámetro aerodinámico medio en masa de 2.5 micrómetros a 4.5 micrómetros con una desviación estándar geométrica menor o igual a 1.8 micrómetros.
- 11El aerosol para usarse de conformidad con cualquiera de las reivindicaciones 1 a 10, en donde el aerosol se produce usando un nebulizador de malla vibrante. 129 ¡NSrnvrtj h:r. y',·. tNDUSTiUAL ·
- 12El aerosol para usarse _de dad eon · cualquiera de las reivindicaciones 1 a humano es tratado concomitantemente seleccionado entre un antibiótico, un 11, en donde el ser con un medicamento broncodilatador, un agente anticolinérgico, un glucocorticoide, un inhibidor eicosanoide o
- 13cualquiera tratamiento medicamento de una combinación de dos o más de los mismos. Un las de un aerosol para usarse reivindicaciones 1 a ser humano de forma seleccionado entre dornasa de 11, conformidad para uso en concomitante con con el un alfa, azitromicina, salbutamol, pancrelipasa, cloruro de sodio hipertónico, seretida, ADEK, o una combinación de dos o más de los mismos.
- 14El aerosol para usarse de conformidad con cualquiera de las reivindicaciones 1 a 13, caracterizado porque comprende además la interrupción de la administración del aerosol durante 28 dias. 130 iNCTiTirrc mexicano >λ:m peu ieuad industrial
Independent claims14
1,508 paragraphs in 141 sections, as filed
(54) Title: USE OF AEROSOLIZED LEVOFLOXACIN FOR THE TREATMENT OF CYSTIC FIBROSIS.
(54) Title: USE OF AEROSOLIZED LEVOFLOXACIN FOR TREATING CYSTIC FIBROSIS.
(57) Summary
The invention relates to methods of treating cystic fibrosis comprising administering to an human in need an aerosol solution comprising levofloxacin or ofloxacin and a bivalent or trivalent cation. The invention relates in particular to the administration of the aerosol solution to a human wherein said human has a lung infection comprising P. aeruginosa.
(57) Abstract
The invention relates to methods for treating cystic fibrosis comprising administering to a human in need thereof an aerosol solution comprising levofloxacin or ofloxacin and a divalent or trivalent cation. The invention relates in particular to administering the aerosol solution to a human where said human has a pulmonary infection comprising P. aeruginosa ..
IMPI
<img file="MX353288B_D0001.tif" />
PATENT TITLE No. 353288
<td>Headlines):</td><td>RAPTOR PHARMACEUTICALS, INC.</td>
<td>D micilio:</td><td>7 Hamilton Landing, Suite 100, Novato, California, 94949, USA</td>
D nomination:
USE OF AEROSOLIZED LEVOFLOXACIN FOR THE TREATMENT OF CYSTIC FIBROSIS.
Classification;
A61K9 / 12; Α6ψ9 «A & 1K3J ^ 383; A61K33 / 06; A61K45 / 06: A61P11 / 00 A61K9 / 12: «¿£ ^ 4oá Í6 ^ <¿/» 078 /; AftlK31 / 5383; A61K33 / 06; A61K33 / 14; A6 & 4fy0fc * 'í) /,
CSetl:, A61K94 / 5383: A61
CIP:
CPC:
Inventor (s):
Núdiero:
MX / a / 2QÍ2 / ^) 2
C
<img file="MX353288B_D0002.tif" />
HAELJS · pUDLEY; DAVID C.
/ * matffonal:
<img file="MX353288B_D0003.tif" />
Validity:
Date sheet
Exp Date
The reference patent is
In accordance with the article from the filing date c
Whoever subscribes to this title is h (Official Gazette of the Federation 25/01/2006, 06/05 / 2009,06 / 01/2010, 06/18 Regulation of the Mexican Institute of articles 1<sup>or</sup>, 3°, 4<sup>or</sup>, 5<sup>or</sup> fraction V subsection a), 16 12/27/1999, amended on 10/10/2002, 07/29/2004, Deputy Generals, Coordinator, Divisional Directors, Departmental Titles and other subordinates of the Mexican Institute on 08/04/2004 and 09/13/2007).
nto: ¿seta n: 8 de e
1/7/2 d Industrial. d% VeimeBíM # m extendable, counted effites the rights.
^ <de1a Industrial Property Law p ^ / 1999, 01/26/2004, 06/16/2005, subsection a), 4<sup>or</sup> and 12th fractions I and III of jW0R | P02. 07/15/2004, 07/28/2004 and 09/07/2007); Mexican Institute of Industrial Property (a sound DOF that delegates powers to regional Directors, Divisional Deputy Directors, and Industrial Coordinators. (DOF 12/15/1999, amended on 02/04/2000, 07/29/2004,
This letter is signed with an advanced electronic signature (FIEL), based on articles 7 BIS 2 of the Industrial Property Law; 3 of its Regulations, and 1 fraction III, 2 fraction V, 26 BIS and 26 TER of the Agreement establishing the guidelines for the use of the Electronic Payment and Services Portal (PASE) of the Mexican Institute of Industrial Property, in the procedures indicated.
THE DIVISIONAL DIRECTOR OF PATENTS
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NAHANNY CANAL REYES
Original string:
NAHANNY MARISOL CANAL REYES | 00001000000403252793 | Administration Service
Tax] 1695 || MX / 2018/2490 | MX / a / 2012/002731 (PCT patent title | 1220 | RRGO | Page (s) | n + 9lpiDpm6P073KxE3MqNNqmqAw =
Digital stamp:
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Arenal No. 550. Floor 1, Pueblo Santa María Tepepan, Xochímilco, 16020,
Mexico City (55) 53340700 wvAY.gob.mx/impi
MX / 2018/2490
35J208
A Λ.-Λ A Λ
USE OF LEVOFLOXACINE AERO SOL IZADA FOR TRAFFOLTEN
CYSTIC FIBROSIS __
RELATED REQUESTS
This application claims priority for US Provisional Application No. 61 / 240,092 filed on September 4, 2009, and US Provisional Application No. 61 / 249,231 filed on October 6, 2009, which are expressly incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
Methods and compositions are provided for treating cystic fibrosis. In particular, compositions and methods are provided for the use of aerosolized levofloxacin to treat cystic fibrosis.
BACKGROUND
Fibrous cystic (CF) patients suffer from chronic lower respiratory tract infections that can be caused by bacteria, including Pseudomonas aeruginosa. Pseudomonas aeruginosa has been particularly problematic to eradicate and has been implicated as the leading cause of morbidity and mortality in CF patients.
Aerosol delivery of antibiotics directly to the lungs has the potential to increase
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<td>the local concentration</td><td>of the antibiotic at the site of</td>
infection, thus improving bacterial destruction compared to systemic administration. Currently, a inhalation tobramycin solution is the only aerosolized antibiotic approved for the management of CF patients with bacteria such as P. aeruginosa. Due to the development of resistance to tobramycin and the limited effect to reduce bacterial density in sputum, there is a need for improved therapies to treat CF patients with lung infections caused by bacteria resistant to multiple drugs, including P. aeruginosa.
SUMMARY
Some embodiments of the present invention relate to compositions, the use of such compositions, and methods of treating cystic fibrosis. Some of such modalities include compositions and methods for the use of aerosolized levofloxacin to treat cystic fibrosis.
Some modalities include methods of treating cystic fibrosis in a human in which the human has a lung infection comprising P. aeruginosa. In some such modalities, the methods include administering to said human in need, an aerosol of a solution comprising levofloxacin or ofloxacin and a bivalent or trivalent cation to achieve a reduction in the density of P. aeruginosa in the sputum of said human by at least 40%, at ιμρι ^> MEXICAN INSTITUTE OF V INDUSTRIAL PROPERTY less 44%, at least 7 0%, at least 90% and at least 97%. Some of these modalities include achieving 'nail' réUüccToñ “'in the density of P. aeruginosa in the sputum of said human by at least 0.25 log CFU / g in sputum, at least 0.50 log CFU / g in sputum, at least 1.0 log CFU / g in sputum, at least 1.5 log CFU / g in sputum and at least 1.8 log CFU / g in sputum.
Some modalities include methods of treating cystic fibrosis in a human including administering to the human in need an aerosol of a solution comprising levofloxacin or ofloxacin and a bivalent or trivalent cation to achieve an increase in FEVi of at least 2% and an increase in FEF 2 5-75 of at least 5%, an increase in FEVi of at least 5% and an increase in FEF 25-75 of at least 10%, an increase in FEVi of at least 7% and an increase in FEF 25- 75 of at least 15%, and an increase in FEVi of at least 10% and an increase in FEF 25-75 of at least 20%.
Some modalities include achieving an increase in FEVi of at least 0.05 L and an increase in FEF 25-75 of at least 0.05 L, an increase in FEVi of at least 0.10 L and an increase in FEF 2 5-75 of at least 0.10 L , an increase in FEVi of at least 0.15 L and an increase in FEF 25-75 of at least 0.15 L, an increase in FEV<sub>X</sub> of at least 0.2 0 L and an increase in FEF 25-75 of at least 0.2 0 L, and an increase in FEVi of at least 0.25 L and an increase in FEF 25-75 of at
IMPI
INSITOITO MEXICAN ': DB LA PRCMF'AJ IND'JSIXML
<img file="MX353288B_D0006.tif" />
minus 0.25 L.
Some modalities include achieving an increase in FEF 25-75 of at least 0.27 L.
Some modalities include methods of treating cystic fibrosis in a human including administering to said human in need an aerosol of a solution comprising levofloxacin or ofloxacin and a bivalent or trivalent cation to achieve a risk ratio of less than 1.0, where the ratio Risk is indicative of a decreased need for other antipseudomonal antimicrobials. In some of these modalities, the risk ratio is less than 0.8, less than 0.6, less than 0.4 and less than 0.3.
Some modalities include methods of treating cystic fibrosis in a human who has been administered an agent by inhalation selected from the group consisting of one or more of dornase alfa, azithromycin, salbutamol, pancrelipase, sodium chloride, seretide, and ADEK, which comprise administering to said human an aerosol of a solution comprising levofloxacin or ofloxacin and a bivalent or trivalent cation. In some embodiments, the agent is selected from the group consisting of salbutamol, pancrelipase, seretide, and ADEK. In some embodiments, the human has a lung infection comprising P. aeruginosa. Some modalities include achieving a reduction in the density of P. aeruginosa in the sputum of said human by at least 0.25
0.50 log CFU / g in sputum and sputum.
Some cystic fibrosis in a human
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INSTITUTO MbXíCAN- 'f
DE! -A INDUSTRIAL LOGO CFU / G in sputum, at least 1.0 log CFU / g in include methods of treating in which the human has a lung infection comprising P. aeruginosa. Some of such modalities include repeatedly administering to said human in need an aerosol of a solution comprising levofloxacin or ofloxacin and a bivalent or trivalent cation, wherein said repeated administration does not result in a greater than 16-fold increase in the minimal inhibitory concentration. (MIC) of the P. aeruginosa strain in said human that has the highest MIC in relation to other P. aeruginosa strains. In some modalities, repeated administration does not result in a greater than 8-fold increase in the minimum inhibitory concentration (MIC) of the P. aeruginosa strain in said human having the highest MIC relative to other P. aeruginosa strains. In some modalities, repeated administration does not result in a greater than 4-fold increase in the minimal inhibitory concentration (MIC) of strain P. aeruginosa in said human that has the highest MIC in relation to other P. aeruginosa strains.
Some modalities include methods of treating cystic fibrosis in a human in which the human has a
<td></td><td>IMPIO * Mexican institute OF IA PROPERTY VV. INDUSTRIAL X</td>
<td>lung infection</td><td>comprising P. aeruginosa. Some of</td>
Such modalities include repeatedly administering to said human in need an aerosol of a solution comprising levofloxacin or ofloxacin and a bivalent or trivalent cation to achieve an increase in a CFQ-R respiratory domain greater than 1, greater than 2, greater than 3, greater than 4 and greater than 5.
Some modalities include methods of decreasing resistance of the minor airways in a human with cystic fibrosis, which comprises administering to said human in need an aerosol of a solution comprising levofloxacin or ofloxacin and a bivalent or trivalent cation to achieve an increase in FEF 25-75 of at least 5%, at least 10%, at least 15% and at least 20%. Some modalities include achieving an increase in FEF 25-75 of at least 0.05 L ·, at least 0.10 L, at least 0.15 L, at least 0.20 L, at least 0.25 L and at least 0.27 L.
Some embodiments include methods of administering levofloxacin or ofloxacin to a human, comprising repeatedly administering to said human an aerosol of a solution comprising levofloxacin or ofloxacin and a bivalent or trivalent cation, wherein said repeated administration does not result in an incidence of arthralgia. In some methods, administration is repeated at least once a day for 14 days, at least one
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w.tutc mexicana υ -'- · Γ, ί ΙΑ ¡TC'isDA '' \ J-.V INDUSTRIAL -M—— once a day for 28 days and at least once a day for 35 days. In some of such methods, administration is repeated at least twice a day for 14 days, at least twice a day for 28 days, and at least twice a day for 35 days.
Some modalities include methods of treating cystic fibrosis in a human in which the human has a lung infection comprising P. aeruginosa and said human has a body surface area of less than 1.5 m.<sup>2</sup>. Some methods include administering to said human in need an aerosol of a solution comprising levofloxacin or ofloxacin and a bivalent or trivalent cation to achieve a normalized serum AUC at the dose of at least 2 0 (ng.h / L) / mg per dose. In some embodiments, the administration is repeated daily for at least 14 days, the aerosol comprises an amount of levofloxacin or ofloxacin of at least 80 mg, 120 mg, 180 mg, and 240 mg.
Some modalities include achieving a dose-normalized serum AUC of at least 20 (ng.h / L) / mg per dose, at least 40 (ng.h / L) / mg per dose, at least 60 (ng.h / L) / mg per dose, at least 80 (ng.h / L) / mg per dose, and at least 100 (ng.h / L) / mg per dose.
Some modalities include methods of treating cystic fibrosis in a human in which the human has a lung infection comprising P. aeruginosa and the human.
<img file="MX353288B_D0008.tif" />
INSTITUTO maxican-j DE LA FROPIF'AÍ) NDUSTRLaL has a body surface area of less than 1.5 m<sup>2</sup>. Some of such methods include administering to said human in need an aerosol of a solution comprising levofloxacin or ofloxacin and a bivalent or trivalent cation to achieve a C<sub>max</sub> in serum normalized by the dose greater than 2 pg / L / mg per administered dose, greater than 4 pg / L / mg per administered dose, greater than 6 pg / L / mg per administered dose, greater than 8 pg / L / mg per administered dose, and greater than 14 pg / L / mg per administered dose. In some modalities, the human is less than 15 years old, less than 12 years old, less than 10 years old. In some embodiments, the human comprises a mass of less than 55 kg, less than 45 kg, less than 35 kg, less than 2 5 kg.
In some of the above modalities, the solution consists essentially of levofloxacin or ofloxacin and the bivalent or trivalent cation.
In some of the above modalities, the solution does not comprise lactose.
In some of the above embodiments, the solution comprises a concentration of the bivalent or trivalent cation from about 50mM to about 400mM, and a concentration of levofloxacin or ofloxacin of between about 50mg / ml and about 200mg / ml.
In some of the above modalities, the solution comprises a concentration of the bivalent cation or
<img file="MX353288B_D0009.tif" />
MEXICAN INSTITUTE
OF THE PROPERTY • NDIISTRJAL
<img file="MX353288B_D0010.tif" />
trivalent from about 100 mM to about 3 00 mM, and a levofloxacin or ofloxacin concentration of between about 75 mg / ml and about 150 mg / ml.
In some of the above embodiments, the solution comprises a concentration of the bivalent or trivalent cation from about 150 mM to about 250 mM, and a concentration of levofloxacin or ofloxacin of between about 90 mg / ml and about 125 mg / ml.
In some of the above embodiments, the solution comprises an osmolality from about 300 mOsmol / kg to about 500 mOsmol / kg, and a pH from about 5 to about 8.
In some of the above embodiments, the solution comprises an osmolality from about 350 mOsmol / kg to about 425 mOsmol / kg and a pH from about 5 to about 6.5.
In some of the above embodiments, the solution comprises a pH of from about 5.5 to about 6.5.
<td colspan="2">In some of</td><td colspan="3">the previous modalities, the cation</td>
<td>bivalent or</td><td>trivalent</td><td>I know</td><td>Choose</td><td>magnesium, calcium,</td>
<td>zinc, copper,</td><td>aluminum and</td><td colspan="2">iron.</td><td></td>
<td>In</td><td>some</td><td>of</td><td colspan="2">the previous modalities, the</td>
solution comprises magnesium chloride.
In some of the previous modalities, the
<td></td><td></td><td></td><td></td>
<td></td><td></td><td>INSTITG7? <sub>t</sub></td><td>'t</td>
<td></td><td></td><td>Ln Γ i VA i 'κ η .. · »- · INfuJYTRJAL ** - · -__ i</td><td></td>
<td>solution comprises a</td><td>concentration of</td><td>levofloxacin</td><td>or</td>
<td>ofloxacin from</td><td>approximately</td><td>90 mg / ml</td><td>and</td>
approximately 110 mg / ml, a magnesium chloride concentration of between approximately 175 mM and approximately
225 mM, a pH of between about 5 and about 7;
an osmolality of between about 300 mOsmol / kg and about 500 mOsmol / kg and lactose free.
In some of the above embodiments, the aerosol comprises a mass median aerodynamic diameter from about 2 microns to about 5 microns with a standard geometric deviation less than or equal to about 2.5 microns.
In some of the above embodiments, the aerosol comprises a mean aerodynamic diameter of mass from about
2.5 micras until approximately
4.5 micras with a standard geometric deviation less than or equal to approximately 1.8 micras.
In some of the above modalities, the aerosol comprises a from about average aerodynamic diameter to mass
2.8 micras to approximately 4.3 micras with a standard geometric deviation less than or equal to approximately 2 micras.
Some of the above modalities also include the production of the aerosol with a vibrating mesh nebulizer. In some such modalities, the nebulizer
IMPI
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Vibrating mesh is a PARI E-FLOW® nebulizer.
In some of the above modalities, the amount of levofloxacin or ofloxacin administered to the lung is at least about 2 0 mg, at least about 100 mg, at least about 125 mg, and at least about 150 mg.
<td>In some</td><td>of</td><td>the</td><td>modalities</td><td>previous,</td><td>to the</td><td>less</td>
<td>about 100</td><td>mg</td><td>of the</td><td>spray it</td><td>manage</td><td>to the</td><td>lung</td>
<td>of the human in less</td><td>of</td><td colspan="2">approximately</td><td>10 minutes,</td><td>in</td><td>less</td>
approximately 5 minutes, in less than approximately 3 minutes and in less than approximately 2 minutes.
Some of the above modalities also include co-administration of an additional active agent selected from the group consisting of antibiotics, bronchodilators, anticholinergics, glucocorticoids, eicosanoid inhibitors, and combinations thereof.
In some embodiments, the antibiotic may include tobramycin, aztreonam, ciprofloxacin, azithromycin, tetracycline, quinupristin, linezolid, vancomycin, and chloramphenicol, collisitin, and combinations thereof. In some modalities, the bronchodilator may include salbutamol, levosalbuterol, terbutaline, fenoterol, terbutaline, pirbuterol, procaterol, bitolterol, rimiterol, carbuterol, tulobuterol, reproterol, salmeterol, formoterol, arformoterol, bambuterol, clenbuterol, indacterol, thedail,
MEXICAN INSTITUTE
LA Γ,: · r'ILCAI)
INCUSIKIAL
<img file="MX353288B_D0012.tif" />
roflumilast, cilomilast and combinations thereof. In some modalities, the anticholinergic can include ipratropium, tiotropium, and combinations thereof.
In some modalities, glucocorticoid may include prednisone, fluticasone, budesonide, mometasone, ciclesonide, beclomethasone, and combinations thereof. In some embodiments, the eicosanoid may include montelukast, pranlukast, zafirlukast, zileuton, ramatroban, seratrodast, and combinations thereof. In some embodiments, co-administration involves inhaling the additional active agent.
Some of the above modalities include administration of the spray once a day.
Some of the above modalities include twice daily aerosol administration.
In some of the above modalities, the lung infection further comprises one or more bacteria that may include
Pseudomonas fluorescens,
Pseudomonas acidovorans, Pseudomonas alkali and Pseudomonas putida, <
> Stenotrophomonas maltophilia,
Aeromonas hydrophilia,
Escherichia coli,
Citrobacter freundii,
Salmonella typhymurium,
Salmonella typhi,
Salmonella paratyphi,
Salmonella enteritidis,
Shigella dysenteriae,
Shigella flexneri, Shigella sonnei,
Enterobacter Cloacae, Enterobacter aerogenes
Klebsiella pneumoniae, Klebsiella oxytoca,
<img file="MX353288B_D0013.tif" />
Serratia marcescens, Morganella morganii, Proteus mirabilis,
Proteus vulgaris, Providencia alcalifaciens. Providencia rettgeri, Providencia stuartii, Acinetobacter calcoaceticus,
Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Oasteurella multocida, Pasteurella haemolytica, Helicobacter pylori, Campylobacter fetus Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholera, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Burkholderia cepacia, Francisella tularensis, Kingella and Moeaxella.
In some of the above modalities, the lung infection further comprises a gram negative anaerobic bacteria.
In some of the above modalities, lung infection further comprises one or more of the bacteria which may include Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii and Bacteroides splanchnicus.
<img file="MX353288B_D0014.tif" />
T Ts fí p T
-TO.
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THE
II; DL-> T1UAL previous modalities, the also a gram bacterium
In some of the pulmonary infections it comprises positive.
In some of the lung infections it comprises bacteria that may include Corynebacterium ulcerans, Streptococcus agalactiae,
<td colspan="2">previous modalities, the</td>
<td>plus one or</td><td>more than</td>
<td>Corynebacterium</td><td>diphtheriae,</td>
<td>Streptococcus</td><td>pneumoniae,</td>
<td>Streptococcus</td><td>pyogenes,</td>
Streptococcus milleri, Streptococcus (Group G), Streptococcus (Group C / F), Enterococcus faecalis, Enterococcus faecium,
Staphylococcus aureus,
Staphylococcus epidermidis,
Staphylococcus saprophyticus, Staphylococcus intermedius,
Staphylococcus hycus subsp.
Hycus,
Staphyl ococcus haemolyticus,
Staphylococcus hominis and
Staphylococcus saccharolyticus.
In some of the above modalities, the lung infection further comprises a gram positive anaerobic bacteria.
In some of the above modalities, the lung infection further comprises one or more bacteria which may include Clostridium difficile, Clostridium perfringens, Clostridium tetini and Clostridium botulinum.
In some of the above modalities, the lung infection further comprises an acid resistant bacteria.
In some of the modalities
<img file="MX353288B_D0015.tif" />
MÍXICAN INSTITUTE-? DF '..A INDUSTRIAL PROPERTY lung infection further comprises one or more bacteria which may include Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare and Mycobacterium leprae.
In some of the above modalities, the lung infection further comprises an atypical bacterium.
In some of the above modalities, the lung infection further comprises one or more bacteria which may include Chlamydia pneumoniae and Mycoplasma pneumoniae.
BRIEF DESCRIPTION OF THE DRAWINGS
Figures 1A and IB show graphs using linear axes and semi-logarithmic axes, respectively, of the mean arithmetic concentrations in serum of levofloxacin after administration of single doses of 180 mg as a 50 mg / ml and 100 mg / ml solution. for inhalation and after administration of 240 mg as a 100 mg / ml solution for inhalation once daily for 7 days to CF patients.
Figures 2A and 2B show graphs using linear axes and semi-logarithmic axes, respectively, of the mean arithmetic concentrations in levofloxacin sputum after administration of single doses of 180 mg as a 50 mg / ml and 100 mg / ml solution. for inhalation and after administration of 240 mg as a 100 mg / ml solution for inhalation once daily for
<img file="MX353288B_D0016.tif" />
MEXICAN INSTITUTE OF INOLÍTRIAL PROPERTY
<img file="MX353288B_D0017.tif" />
days to CF patients. _.................
Figure 3 shows a graph of the mean change 'in P. aeruginosa (loglO CFU / g in sputum) over time during various treatment arms in a US patient population. Patients were administered: levofloxacin 120 mg daily, levofloxacin 240 mg daily, levofloxacin 240 mg twice daily, or placebo.
Figure 4 shows a graph of the change in P. aeruginosa (loglO CFU / g in sputum) over time during various treatment arms in a population of MITT patients. The patients were administered: levofloxacin 120 mg per day, levofloxacin 240 mg per day, levofloxacin 240 mg twice a day, or placebo.
Figure 5 shows a graph of the survival distribution function over time for various treatment groups in an EE population.
Figure 6 shows a graph of the survival distribution function over time for various treatment groups in a MITT population.
Figure 7 shows a graph of the percent change in FEVi (L) on Day 28 for the EE population treated with placebo, 120 mg per day, 240 mg per day or 240 mg twice a day.
Figure 8 shows a graph of the percentage change in FEVi (L) vs. Placebo on Day 28 for RR population treated with 120 mg per day,
240 mg twice a day. * p = 0.0102.
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L'íTIT'm. MEXICANO DE LX l-RÜHEDAD industrial
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240 mg per day, or
Figure 9 shows a graph of the predicted percentage change in FEVi on Day 28 for the EE population treated with 120 mg per day, 240 mg per day, or 240 mg twice a day. * p - 0.0370, ** p - 0.0037.
Figure 10 shows a graph of serum AUC normalized by dose (ng.h / L / mg per dose) vs. the body weight of the pediatric CF patient (180 mg (n = 7); ♦
240 mg (n = 18)). The mean value is shown for serum levofloxacin AUC in adult CF patients studied in another clinical trial (not shown) and based on a mean weight of 71 kg (▲; +/- standard deviation).
Figure 11A shows a plot of serum AUC normalized by dose (ng.h / L / mg per dose) vs. the age of the CF patient (180 mg; ♦ 240 mg). Figure 11B shows a plot of serum AUC normalized by dose (ng.h / L / mg per dose) vs. the BSA (body surface area) (180 mg; ♦ 240 mg). Figure 11C shows a graph of C<sub>max</sub> serum normalized by dose (pg / L / mg per administered dose) vs. the body weight of a pediatric CF patient (180 mg; ♦ 240 mg). Figure 11D shows a graph of the C<sub>max</sub> serum normalized by dose (pg / L / mg per administered dose) vs. the age of a pediatric CF patient (180 mg; ♦ 240 mg). Figure 11E shows r
a graph of
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MEXICAN INSTITUTE
DELA nONSDAP
INtHlSTKLAL
<img file="MX353288B_D0019.tif" />
the C<sub>max</sub> serum normalized by dose (pg / L / mg per administered dose) vs. BSA (180 mg; ♦ 240
DETAILED DESCRIPTION
The present invention relates to the use of particular formulations of levofloxacin solutions for inhalation and to particular dosing and administration regimens for the treatment of cystic fibrosis. In some modalities, the treatment of cystic fibrosis includes the treatment of lung diseases associated with cystic fibrosis, such as P. aeruginosa, S.
pneumoniae, H. influenzae, Burkholderia sp., Staphylococcus aureus, Stenotrophomonas sp., and M. catarrhalis. The methods described herein for treating cystic fibrosis can include administering levofloxacin formulations. In some embodiments, methods of treating cystic fibrosis may also include achieving a reduction in the density of particular pathogens in a subject's lungs. In some modalities, methods of treating cystic fibrosis may also include improving the lung characteristics of a subject that can be measured with parameters such as FEVi, FEF 25-72, and the like.
The present invention provides various advantages. For example, aerosolized levofloxacin delivers high doses of the drug directly to the lung.
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tNSTITUn: MEKKa.í-'O ιλ o
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High doses are advantageous in reducing the development of resistant strains. Furthermore, the present invention provides formulations with reduced adverse effects typically associated with fluoroquinones, such as arthralgia. Some modalities provide methods of treating cystic fibrosis that decrease the risk of acute exacerbations in CF patients at risk of exacerbations. More modalities provide methods to increase air flow in the lungs of CF patients. In various embodiments, the above methods are accomplished by administering levofloxacin or ofloxacin aerosol in doses and schedules of administration sufficient to achieve the stated result.
Definitions
The term administration or administering refers to a method of providing a dose of an antimicrobial pharmaceutical composition to a vertebrate. The preferred method of administration may vary depending on various factors, eg, the components of the pharmaceutical composition, the actual or potential site of the bacterial infection, the microbe involved, and the severity of an actual microbial infection. In some embodiments, administration may include loading an instrument to deliver a drug to a subject. In some embodiments, administration may include loading a nebulizer with a drug to be delivered to a patient. By
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<img file="MX353288B_D0022.tif" />
Therefore, the administered dose can be the dose loaded in the instrument (eg, the nebulizer).
A vehicle or excipient is a compound or material used to facilitate administration of the compound, for example, to increase the solubility of the compound. Solid vehicles include, eg, starch, lactose, dicalcium phosphate, sucrose, and kaolin. Liquid vehicles include, eg, sterile water, saline, buffers, nonionic surfactants, and edible oils such as peanut and sesame oils. In addition, various adjuvants such as those commonly used in the art can be included. These and other such compounds are described in the literature, eg, in the Merck Index, Merck & Company, Rahway, NJ. Considerations for the inclusion of various components in pharmaceutical compositions are described, eg, in Gilman et al., (Eds) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8<sup>8</sup> ed., Pergamon Press, incorporated by reference herein in its entirety.
A diagnosis as used herein is a compound, method, system, or device that aids in the identification and characterization of a state of health or disease. The diagnosis can be used in standard assays as known in the art.
<img file="MX353288B_D0023.tif" />
1KTITUTO MEXICANO Dt LA
INU'JHTaíAL
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The term mammal is biologically common. Therefore, it includes uses in its sense specifically humans, cattle, horses, dogs and cats, but it also includes many other species.
The term microbial infection refers to the proliferation or unwanted presence of an invasion of pathogenic microbes in a host organism. This includes the overgrowth of microbes that are normally present in or on the body of a mammal or other organism. More generally, a microbial infection can be any situation in which the presence of a microbial population (s) is damaging a host mammal. Thus, a microbial infection exists when an excessive number of a microbial population is present in or on the body of a mammal, or when the effects of the presence of a microbial population (s) is damaging cells or other tissue of a mammal.
The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coating, antibacterial and anti-fungal agent, isotonic and absorption retarding agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except when any conventional media or agent is incompatible with the active ingredient,
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contemplates its use in pharmaceutical compositions. Supplemental active ingredients can also be incorporated into the compositions.
The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the compounds of this invention and that are not biologically or otherwise undesirable. In many cases, the compounds of this invention are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
Organic acids from which the salts can be derived include, for example, acetic acid, propionic acid, naphthoic acid, oleic acid, palmitic acid, pamoic (emboic) acid, stearic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid , malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, ascorbic acid, glucoheptonic acid, glucuronic acid, lactic acid, lactobioic acid, tartaric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, acid
P-
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INSTITUTO MEXICANO DI LA PROPERTY INDUSTRIA!
<img file="MX353288B_D0027.tif" />
toluenesulfonic of addition of salicylic acid and the like. Salts
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Pharmaceutically acceptable can be formed with inorganic and organic bases.
Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine. , trimethylamine, diethylamine, triethylamine, tripropylamine, histidine, arginine, lysine, benetamine, N-methyl-glucamine and ethanolamine. Other acids include dodecyl sulfuric acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, and saccharin.
Solvate refers to the compound formed by the interaction of a solvent and antimicrobial fluoroquinolone, a metabolite, or a salt thereof. Suitable solvates are pharmaceutically acceptable solvates that include hydrates.
In the context of the response of a microbe, such as a bacterium, to an antimicrobial agent, the term
IMPI
INSTITUTO MEXICANO b £ LA MOHEDA!) INDUSTRIAL susceptibility refers to the sensitivity of the microbe to the presence of the antimicrobial agent. Therefore, increasing susceptibility means that the microbe will be inhibited by a lower concentration of the antimicrobial agent in the medium surrounding the microbial cells. This is equivalent to saying that the microbe is more sensitive to the antimicrobial agent. In most cases the minimum inhibitory concentration (MIC) of that antimicrobial agent will have been reduced. The MIC<sub>90</sub> it can include concentration to inhibit growth in 90% of organisms.
By therapeutically effective amount or pharmaceutically effective amount is meant a fluoroquinolone antimicrobial agent, as described for this invention, which has a therapeutic effect. The doses of the fluoroquinolone antimicrobial agent that are useful in the treatment are therapeutically effective amounts. Therefore, as used herein, a therapeutically effective amount means those amounts of the fluoroquinolone antimicrobial agent that produce the desired therapeutic effect calculated by the results of a clinical test and / or infection studies in animal models. In particular embodiments, the fluoroquinolone antimicrobial agent is administered in a predetermined dose, and therefore a therapeutically amount.
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This . iNtrrnnc ·>
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Effective INDUCTKIAL would be an amount of the administered dose, amount and the amount of the fluoroquinolone antimicrobial agent can be routinely determined by the person skilled in the art and will vary depending on various factors, such as the particular microbial strain involved. This amount may also depend on the height, weight, sex, age and medical history of the patient. For prophylactic treatments, a therapeutically effective amount is that amount that would be effective in preventing a microbial infection.
A therapeutic effect relieves, to some extent, one or more of the symptoms of infection, and includes the cure of an infection. Curing means that the symptoms of active infection are eliminated, including the total or substantial elimination of excessive members of the viable microbe from those involved in the infection to a point at or below the detection threshold by traditional measurements. However, there may be certain long-term or permanent effects of the infection after obtaining a cure (such as extensive tissue damage). As used herein, a therapeutic effect is defined as a statistically significant reduction in bacterial load in a host, in the emergence of resistance, or an improvement in symptoms of infection measured by clinical results in humans or in studies in
- 26 animals.
Treat, treat or treat as you
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MEXICAN INSTITUTE OF THE MCPIF. 'AU
INDUSTRIAL
<img file="MX353288B_D0031.tif" />
Used herein refers to the administration of a pharmaceutical composition for prophylactic and / or therapeutic purposes. The term prophylactic treatment refers to the treatment of a patient who is not yet infected, but who is susceptible to, or is otherwise at risk of, a particular infection such that there is a reduction in the onset of infection. The term therapeutic treatment refers to the administration of the treatment to a patient already suffering from an infection. Thus, in preferred embodiments, the treatment is the administration to a mammal (for either therapeutic or prophylactic purposes) of therapeutically effective amounts of a fluoroquinolone antimicrobial agent.
Pharmacokinetics (PK) is concerned with the time course of the concentration of the antimicrobial in the body. Pharmacodynamics (PD) is concerned with the relationship between pharmacokinetics and antimicrobial efficacy in vivo. PK / PD parameters correlate antimicrobial exposure with antimicrobial activity. The rate of destruction by the antimicrobial depends on the mode of action of the antimicrobial and is determined by either the length of time necessary to destroy (time dependent) or by
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Mexican INSTITUTE
Μ Ι.Λ TRCRIIDAD
INl -USTRi / RL
<img file="MX353288B_D0033.tif" />
the effect of increasing concentrations (concentration dependent). Different PK / PD parameters can be used to predict the therapeutic efficacy of antimicrobials with various mechanisms of action. PK / PD parameters can be used to determine the bioavailability of antimicrobial compositions, eg, the bioavailability of a composition in the pulmonary system, and / or the bioavailability of a plasma / serum composition.
The AUC / MIC ratio is an example of a PK / PD parameter. AUC is defined as the area under the plasma / serum concentration-time curve or at the site of infection of an antimicrobial agent in vivo (in animal or human). For example, the site of infection and / or the site where concentration is measured can include portions of the pulmonary system, such as bronchial fluid and / or sputum. Accordingly, AUC may include serum AUC, and pulmonary AUC. The AUC<sub>(0</sub>-t) can include the area under the curve for time zero towards a specific time
AUC (o-inf) can include the area under the curve from time zero to infinity.
The relationship of
AUC / MIC is determined by dividing the
AUC of hours for an individual antimicrobial between the
MIC for the same antimicrobial determined in vitro.
Antimicrobial activity with dose dependent destruction (such as fluoroquinolones) is highly predictable by the
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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY
<img file="MX353288B_D0034.tif" />
magnitude of the AUC / MIC ratio.
C's ratio<sub>max</sub>: MIC is another parameter of
PK: PD. This describes the maximum concentration of the drug in plasma or tissue in relation to MIC. Fluoroquinolones and aminoglycosides are examples where C<sub>max</sub>: MIC can predict bacterial destruction in vivo where resistance can be suppressed.
<td></td><td>The</td><td>weather</td><td>above MIC</td><td> (T> MIC) is</td><td>other</td>
<td>parameter</td><td>of</td><td>PK / PD.</td><td>This is expressed as</td><td>a percentage</td><td>of a</td>
<td>interval</td><td>of</td><td colspan="2">dose at which level</td><td>in plasma or</td><td>at</td>
<td>site of</td><td colspan="2">infection</td><td>exceeds MIC. The</td><td colspan="2">activity of the</td>
Antimicrobials with time-dependent destruction (such as beta-lactams or oxazolidinones) are highly predictable due to the magnitude of the T> MIC ratio.
The term "dosing interval" refers to the time between administrations of the two sequential doses of a pharmacist during multiple dosing regimens. For example, in the case of orally administered ciprofloxacin, which is administered twice daily (traditional 400 mg twice daily regimen) and orally administered levofloxacin, which is administered once daily (500 mg or 750 mg per day), the dosing intervals are 12 hours and 24 hours, respectively.
As used herein, the peak period
INSTITUTE MEX1C V ',' 0 OF THE «0f« .0AU of the pharmacist's in vivo concentration, the time of the dosage interval — dol f armaeéut ± ctr ~ · is set when the concentration of the pharmacist is not less than 50% of its maximum concentration in plasma or at the site of infection. In some modalities, peak period is used to describe an antimicrobial dosing interval.
The respirable dose delivered is the amount of the drug inhaled during the inspiratory phase of the breathing simulator that is equal to or less than 5 microns using a simulator programmed for the European standard standard of 15 breaths per minute, with an inspiration-to-expiration ratio of 1 :one.
Pharmaceutical Compositions
For purposes of the method described herein, a fluoroquinolone agent formulated with a bivalent or trivalent cation having improved lung bioavailability can be administered using an inhaler. In some embodiments, the antimicrobial fluoroquinolone described herein is produced as a pharmaceutical composition suitable for aerosol formation, good tasting, with storage stability, and patient safety and tolerability. In some embodiments, the content of the manufactured fluoroquinolone isoform can be optimized for tolerability, antimicrobial activity, and stability.
may include a cation ' <sup>1 1</sup> > ··· * ··· β · ΙΙ> · ι ·· Κ »« ί «· 1ΐ || · ΙΒ ·» »· TUL« jin, 1
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MEXICAN INSTITUTE OF INDUSTRIAL TRONEDAD
<img file="MX353288B_D0035.tif" />
Bivalent or trivalent formulations. The bivalent or trivalent cation can include, for example, magnesium, calcium, zinc, copper, aluminum, and iron.
In some embodiments, the solution comprises magnesium chloride, magnesium sulfate, chloride
<td colspan="7">zinc, or copper chloride. In some modalities,</td><td>the</td>
<td colspan="3">cation concentration</td><td colspan="2">bivalent</td><td colspan="2">or trivalent can</td><td>to be</td>
<td>since</td><td>approximately</td><td> 25</td><td>mM</td><td>until</td><td>approximately</td><td> 400</td><td>mM,</td>
<td>since</td><td>approximately</td><td> 50</td><td>mM</td><td>until</td><td>approximately</td><td> 400</td><td>mM,</td>
<td>since</td><td>approximately</td><td> 100</td><td>mM</td><td>until</td><td>approximately</td><td> 300</td><td>mM,</td>
<td>since</td><td>approximately</td><td> 100</td><td>mM</td><td>until</td><td>approximately</td><td> 250</td><td>mM,</td>
<td>since</td><td>approximately</td><td> 125</td><td>mM</td><td>until</td><td>approximately</td><td> 250</td><td>mM,</td>
<td>since</td><td>approximately</td><td> 150</td><td>mM</td><td>until</td><td>approximately</td><td> 250</td><td>mM,</td>
<td>since</td><td>approximately</td><td> 175</td><td>mM</td><td>until</td><td>approximately</td><td> 225</td><td>mM,</td>
<td>since</td><td>approximately</td><td> 180</td><td>mM (</td><td colspan="4">up to approximately 220 mM, and</td>
<td>since</td><td>approximately</td><td> 190</td><td>mM</td><td>until</td><td>approximately</td><td> 210</td><td>mM.</td>
magnesium sulfate
In some embodiments, magnesium chloride, zinc chloride, or copper chloride can have a concentration of approximately
5% up to approximately
25%, from about 10% to about 20%, and from about 15% to about 20%. In some embodiments, the ratio of fluoroquinolone to bivalent or trivalent cation can be 1: 1 to 2: 1 or 1: 1 to 1: 2.
Non-limiting fluoroquinolones for use as described ofloxacin, herein ciprofloxacin, gemifloxacin, lomefloxacin,
IMPIféf
MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY include levofloxacin,
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enoxacin moxifloxacin, gatifloxacin, norfloxacin, pefloxacin, esparfloxacin, garenoxacin, sitafloxacin and DX
619.
The formulation may have a concentration of fluoroquinolone, for example levofloxacin or ofloxacin, greater up to about 50 mg / ml, about 60 mg / ml, about 70 mg / ml, about 80 mg / ml,
<td>approximately</td><td> 90</td><td>mg / ml,</td><td>approximately</td><td> 100</td><td>mg / ml,</td>
<td>approximately</td><td> 110</td><td>mg / ml,</td><td>approximately</td><td> 120</td><td>mg / ml,</td>
<td>approximately</td><td> 130</td><td>mg / ml,</td><td>approximately</td><td> 140</td><td>mg / ml,</td>
<td>approximately</td><td> 150</td><td>mg / ml,</td><td>approximately</td><td> 160</td><td>mg / ml,</td>
<td>approximately</td><td> 170</td><td>mg / ml,</td><td>approximately</td><td> 180</td><td>mg / ml,</td>
about 190 mg / ml, and about 200 mg / ml. In some embodiments, the formulation may have a concentration of fluoroquinolone, for example levofloxacin or ofloxacin, from about 50 mg / ml to about 200 mg / ml, from about 75 mg / ml to about 150 mg / ml, from about 80 mg / ml to approximately 125 mg / ml, from approximately 80 mg / ml to approximately 120 mg / ml, from approximately 90 mg / ml to approximately 125 mg / ml, from about 90 mg / ml to about 120 mg / ml, and from about 90 mg / ml to about
110 mg / ml.
The formulation can have an osmolality from about 300 mOsmol / kg, from about
450 mOsmol / kg to approximately mOsmol / kg. In formulation it is approximately approximately approximately
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INSTITUTr> MÍXICANu!> [IA Plri WU mo industrial
<img file="MX353288B_D0037.tif" />
mOsmol / kg to approximately 500 approximately 325 mOsmol / kg to mOsmol / kg, from approximately 350 approximately 425 mOsmol / kg, and from
350 mOsmol / kg up to some modalities, approximately 400 the highest osmolality up to approximately 300 mOsmol / kg,
325
375
425 mOsmol / kg, mOsmol / kg, mOsmol / kg, approximately approximately approximately
350
400
450 mOsmol / kg, mOsmol / kg, mOsmol / kg, approximately
475 mOsmol / kg, and approximately 500 mOsmol / kg.
from
The formulation may have a pH of
<td>about4</td><td> .5</td><td>until</td><td>approximately</td><td> 8.5,</td><td>from</td>
<td>approximately</td><td> 5.0</td><td>until</td><td>approximately</td><td> 8.0,</td><td>from</td>
<td>approximately</td><td> 5.0</td><td>until</td><td>approximately</td><td> 7.0,</td><td>from</td>
<td>approximately</td><td> 5.0</td><td>until</td><td>approximately</td><td> 6.5,</td><td>from</td>
<td>approximately</td><td> 5.5</td><td>until</td><td>about 6.</td><td>.5 and</td><td>from 6.0</td>
up to about 6.5.
The formulation may comprise a conventional pharmaceutical carrier, an excipient, or the like (eg, mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, croscarmellose sodium, glucose,
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M'XiC / .N. INSTITUTE ·
FROM U PROPüC'O iriDUSTKIAi
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gelatin, sucrose, magnesium carbonate, and the like), or auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents, and the like (eg, sodium acetate, sodium citrate, cyclodextrin derivatives , sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate and the like).
In some embodiments, the formulation may lack a pharmaceutical vehicle, an excipient, or the like.
Some modalities include a formulation that lacks lactose.
Some modalities include lactose a lower concentration up to approximately 10%,
5%,
1% or
0.1%. In some embodiments, the formulation may consist essentially of levofloxacin or ofloxacin and a bivalent or trivalent cation.
In some embodiments, a formulation may comprise a levofloxacin concentration of between about 75mg / ml and about 150mg / ml, a magnesium chloride concentration of between about 150mM and about 250mM, a pH of between about 5 and about 7; an osmolality of between about 300 mOsmol / kg and about 500 mOsmol / kg and lactose free.
In some embodiments, a formulation comprises a concentration of levofloxacin from approximately 100 mg / ml, a concentration of magnesium chloride from
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MEXICAN INSTITUTE '
Dt INDUSTRIAL PROPERTY
<img file="MX353288B_D0040.tif" />
about 200 mM, a pH from about 6.2, an osmolality from about 383 mOsmol / kg and lactose-free. In some embodiments, a formulation consists essentially of a levofloxacin concentration from about 100 mg / ml, a magnesium chloride concentration from about 200 mM, a pH from about 6.2, an osmolality from about 383 mOsmol / kg, and lactose free. In some embodiments, a formulation consists of a levofloxacin concentration of about 100 mg / ml, a magnesium chloride concentration of about 2 00 mM, a pH of about 6.2, an osmolality of about 383 mOsmol / kg, and lactose free.
In some embodiments, fluoroquinolone aerosol therapy can be administered as a treatment or prophylaxis in combination or in alternate therapeutic sequence with other oral or parenteral aerosol antibiotics. As a non-limiting example this may include tobramycin and / or another aminoglycoside, aztreonam, carumonam and tigemonam and / or another beta or mono-lactam, ciprofloxacin and / or other fluoroquinolones, azithromycin and / or other macrolides or ketolides, tertacycline and / or other quinupristin
<img file="MX353288B_D0041.tif" />
other streptogramins, tetracyclines,
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glycopeptides others
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vancomycin
<img file="MX353288B_D0044.tif" />
others and chloramphenicol and / or other phenicols and
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collisitin and / or other polymyxins. In more modalities, the antibiotic may include quinolones, tetracyclines,
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<img file="MX353288B_D0047.tif" />
glycopeptides, aminoglycosides, β-lactams, rifamycins, macrolides / ketolides, oxazolidinones, coumericines, chloramphenicol, streptogramins, trimethoprim, sulfamethoxazole, or polymyxins. In particular embodiments, an antibiotic of the above classes can be, for example, one of the following. In some embodiments, any of the above antibiotics can be administered by any acceptable method or route, eg, by aerosol, orally or parenterally.
Beta-lactam antibiotics
Antibiotics of beta-lactam include, but are not limited to, imipenem, meropenem, biapenem, cefaclor, cefadroxil, cefamandole, cefatrizine, Cefazedone, cefazolin, cefixime, cefmenoxime, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotiam, cefpimizole, cefpyramide, cefpodoxime, cefsulodin, ceftazidime, cefteram, ceftezol, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, cefuzonam, cefaacetrile, cefalexin, cefaloglycin, cefaloridine, cefalotin, cefapirin, cefapirin cefmetazol, cefoxitin, cefotetan, aztreonam, carumonam, flomoxef, moxalactam, amidinocilin, carbencilina, dicloxacillin, amoxicillin, benzylpenicillin, methicillin, ampicillin, carfecillin, mezlocillin, azlocycline, cloxacillin,
<img file="MX353288B_D0048.tif" />
IMPI
MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY exacillin, penicillin G, piperacillin, sulbenicillin, temocillin, ticarcillin, cefditoren, SC004, KY-020, cefdinir, ceftibuten, FK-312, S-1090, CP-0467, BK-218, FK-037 , DQ-2556, FK-518, .cefozopram, ME1228, KP-736, CP-6232, Ro 09.1227, OPC20000, and LY206763.
Macrolides
Macrolides include, but are not limited to, azithromycin, clarithromycin, erythromycin, oleandomycin, rokitamycin, rosaramycin, roxithromycin, and troleandomycin.
Ketolides
Ketolides include, but are not limited to, telithromycin and cetrimycin.
Quinolones
Quinolones include, but are not limited to, amifloxacin, cinoxacin, ciprofloxacin, enoxacin, fleroxacin, flumequine, lomefloxacin, nalidixic acid, norfloxacin, ofloxacin,
1evo f1oxaxc ina, oxolinic acid, pefloxacin, rosoxacin, temafloxacin, tosufloxacin, sparfloxzacin, clinafloxacin, moxifloxacin, gemifloxacin;
garenofloxacin, PD131628,
PD138312, PD140248,
Q-35, AM-1155,
NM394, T-3761, rufloxacin,
OPC-17116, DU-6859a (see,
eg,
Sato K., et al., 1992,
Antimicrob Agents
Chemother., 37: 1491-98), and DV-7751a (see,
eg, Tanaka M., et al., 1992, Antimicrob. Agents Chemother.,
37:2212-18).
Tetracyclines, Glycylcyclines and
Oxazolidinones
- 37 IMPI
MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY
<img file="MX353288B_D0049.tif" />
Tetracyclines, glycylcyclines, and oxazolidinones include, but are not limited to, chlortetracycline, demeclocycline, doxycycline, limecycline, metacycline, minocycline, oxytetracycline, tetracycline, tigecycline, linezolid, and eperozolid.
Aminoglycosides
Aminoglycosides include, but are not limited to amikacin, arbekacin, butyrosine, dibekacin, fortimycin, gentamicin, kanamycin, meomycin, netilmycin, ribostamycin, sisomycin, spectinomycin, streptomycin, and tobramycin.
Lincosamides
Lincosamides include, but are not limited to, clindamycin and lincomycin.
Streptogramins
Streptogramins include, but are not limited to, quinupristine.
Glycopeptides
Glycopeptides include, but are not limited to, vancomycin.
Polymyxins
Polymyxins include, but are not limited to, colysitin.
More examples include phosphomycin, penicillins, cephalosporins, carbapenems, penems, and carbacephems.
F; ;
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7 / J Ί
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In some embodiments, a formulation includes a fluoroquinolone in combination - with an additional active agent.
As discussed herein, some such additional active agents may include antibiotics. More additional active agents may include bronchodilators, anticholinergics, glucocorticoids, eicosanoid inhibitors, and combinations thereof. Examples of bronchodilators include salbutamol, levosalbuterol, terbutaline, fenoterol, terbutaline, pirbuterol, procaterol, bitolterol, rimiterol, carbuterol, tulobuterol, reproterol, salmeterol, formoterol, arformoterol, bambuterol, clenbuterol, indacterol, rheophylline, rheophyllin, rheophyllin, rheophyllin, rheophyllin, rheophyllin, rheophyllin, rheophyllin, rheophyllin, rheophyllin, rheophyllin, rheophyllin, rheophyllin, rheophyllin, rheophyllin, rheophyllin, rheophyllin, rheophyllin, rheophyllin, rheophyllin, rheophyllin, rheophyllin, rheophylline, rheophyllin.
Examples of anticholinergics include ipratropium and tiotropium.
Examples of glucocorticoids include prednisone, fluticasone, budesonide, mometasone, ciclesonide, and beclomethasone.
Examples of eicosanoids include montelukast, pranlukast, zafirlukast, zileuton, ramatroban, and seratrodast. More additional active agents may include pulmozyme, hypertonic saline, agents that restore the function of the chloride channel in
CF, inhaled beta-agonists, inhaled antimuscarinic agents, inhaled corticosteroids, and inhaled phosphodiesterase inhibitors.
In some modalities, aerosol antibiotic therapy given as a treatment or prophylaxis can
<img file="MX353288B_D0050.tif" />
IMPI
MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY used in combination or alternating the therapeutic sequence with an additional active agent. In more modalities, the additional active agent can be administered as a treatment, alone, co-formulated, or administered with aerosol antibiotic therapy.
Administration
Bivalent or trivalent formulated fluoroquinolone antimicrobial cations can be administered at a therapeutically effective dose,
eg, a dose sufficient to achieve the results described herein.
Similarly, the manner and schedule of administration can be selected to achieve the results described herein. For example, in some modalities, the respirable dose administered to the lungs can be from about mg to about
170 mg, from about 30 mg to about 160 mg, from about 40 mg to about 150 mg, from about mg to about 140 mg, and mg to about 130 mg. In from about
<td colspan="3">some modalities,</td><td colspan="3">the loaded dose can</td><td>to be</td>
<td>approximately</td><td> 80</td><td>mg</td><td>until</td><td>approximately</td><td> 280</td><td>mg,</td>
<td>approximately</td><td> 90</td><td>mg</td><td>until</td><td>approximately</td><td> 270</td><td>mg,</td>
<td>approximately</td><td> 100</td><td>mg</td><td>until</td><td>approximately</td><td> 260</td><td>mg,</td>
<td>approximately</td><td> 110</td><td>mg</td><td>until</td><td>approximately</td><td> 250</td><td>mg and</td>
<td>approximately</td><td> 120</td><td>mg</td><td>until</td><td>approximately</td><td> 240</td><td>mg.</td>
from from from from from
In
<img file="MX353288B_D0051.tif" />
¡NlfflTUTO MEXICANO »F. INDUSTRIAL PROPERTY
<img file="MX353288B_D0052.tif" />
particular modalities the dose can. admínÍcbr<sub>to</sub>r.ca · daily or twice a day. In some modalities, therapy is administered for at least 28 days.
Administration of the fluoroquinolone antimicrobial agents described herein or the pharmaceutically acceptable salts thereof can be through any of the modes of administration for agents that serve similar uses including, but not limited to, aerosol inhalation. Delivery methods, devices and compositions are described in US Patent Application Publication No. 2006-0276483, incorporated by reference in its entirety.
Pharmaceutically acceptable compositions include solid, semi-solid, liquid, and aerosol dosage forms, such as, for example, powders, liquids, suspensions, compositions, liposomes, particles, or the like. Preferably, the compositions are provided in suitable unit dose forms for single administration of a precise dose.
<td>The</td><td>agent</td><td colspan="2">antimicrobial in</td><td colspan="2">spray can</td>
<td>manage</td><td>either</td><td colspan="2">alone or in some</td><td colspan="2">alternatives in</td>
<td>combination</td><td>with a</td><td>vehicle,</td><td colspan="2">excipient or what</td><td>Similary</td>
<td>pharmacist</td><td colspan="2">conventional (eg,</td><td>mannitol,</td><td>lactose,</td><td>starch,</td>
<td>stearate</td><td>magnesium,</td><td>saccharin</td><td>of sodium,</td><td>talcum powder,</td><td>cellulose,</td>
<td>croscarmellose</td><td colspan="4">sodium, glucose, gelatin,</td><td>saccharose,</td>
<img file="MX353288B_D0053.tif" />
<img file="MX353288B_D0054.tif" />
magnesium carbonate, and the like).
If desired, the pharmaceutical composition may also contain minor amounts of non-toxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents, and the like (eg, sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate and the like).
Generally, depending on the intended mode of administration, the pharmaceutical formulation will contain from about 0.005% to 95%, preferably from about 0.5% to 50%, by weight of a compound of the invention. Current methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art, for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.
In a preferred embodiment, the compositions will take the form of a unit dose form such as a vial containing a liquid, solid for suspension, dry powder, lyophilate, or other composition and thus the composition may contain, together with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, acacia gum, polyvinylpyrrolidone, gelatin, cellulose, derivatives of
<img file="MX353288B_D0055.tif" />
administrable compositions
IMPI
ΜΕΛICANO INSTITUTE
LE 1Λ PROPERTY LJ INOUSTRiAl cellulose or the like.
For example, pharmaceutically liquids can be prepared by dissolving, dispersing, etc., an active compound as defined above and optional pharmaceutical adjuvants in a vehicle (eg, water, saline, aqueous dextrose, glycerol, glycols, ethanol, or the like) to form a solution or suspension. Solutions to be formulated in aerosol can be prepared in conventional forms either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to production and inhalation of the aerosol. The percentage of the active compound contained in such aerosol compositions is highly dependent on the specific nature thereof, as well as on the activity of the compound and the needs of the subject. However, percentages of the active ingredient from 0.01% to 90% in solution can be used, and will be higher if the composition is a solid, which will subsequently be diluted to the above percentages. In some embodiments, the composition will comprise from 1.0% to 50.0% of the active agent in solution.
In some embodiments of the methods, compositions, and uses provided herein, the duration of a therapy, eg, an aerosol antibiotic therapy, may include at least about 1 day / month, at
<img file="MX353288B_D0056.tif" />
minus approximately 2 days / month, at least approximately 3 days / month, at least approximately 4 days / month, at least approximately 5 days / month, at least approximately 6 days / month, at least approximately 7 days / month, at least approximately 8 days / month, at least approximately 9 days / month, at least approximately 10 days / month, at least approximately 11 days / month, at least approximately 12 days / month, at least approximately 13 days / month, at least approximately 14 days / month, at least about 15 days / month, at least about 16 days / month, at least about 17 days / month, at least about 18 days / month, at least about 19 days / month, at least about 20 days / month, at least about 21 days / month , at least approximately 22 days / month, at least approximately 23 days / month, at least approximately 24 days / month, at least approximately 25 days / month, at least approximately 26 days / month, at least approximately 27 days / month, at least about 28 days / month, at least about 29 days / month, at least about 30 days / month, and at least about 31 days / month.
The compositions described herein can be administered with a frequency of about 1, 2, 3, 4 or more times a day, 1, 2, 3, 4, 5, 6, 7 or more times a week, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times a month. In particular embodiments, the compositions are administered
<img file="MX353288B_D0057.tif" />
MEXICAN INSTITUTE Dt THE INDUSTRIAL PROPERTY
<img file="MX353288B_D0058.tif" />
twice daily.
Aerosol Supply
For pulmonary administration, the upper airways are avoided in favor of the middle and lower airways. Pulmonary delivery of the drug can be accomplished by inhaling an aerosol through the mouth and throat. Particles that have a mass mean aerodynamic diameter (MMAD) of more than about 5 microns generally do not reach the lung; instead they tend to collide with the back of the throat and be swallowed and possibly orally absorbed. Particles with diameters from about 2 to about 5 microns are small enough to reach the upper middle lung region (conduction airways), but are too large to reach the alveoli. The smallest particles, ie, from about 0.5 to about 2 microns, are capable of reaching the alveolar region. Particles having diameters smaller than about 0.5 microns can also be deposited in the alveolar region by sedimentation, although very small particles can be exhaled.
In one embodiment, a nebulizer is selected on the basis of allowing the formation of an aerosol of a fluoroquinolone antimicrobial agent described herein which
<img file="MX353288B_D0059.tif" />
it has a predominantly MMAD of between about 2 and about 5 microns. In one embodiment, the delivered amount of the fluoroquinolone antimicrobial agent provides a therapeutic effect for respiratory infections. The nebulizer can deliver an aerosol comprising a mass median aerodynamic diameter from about 2 microns to about 5 microns with a standard geometric deviation less than or equal to about 2.5 microns, a median mass aerodynamic diameter from about 2.5 microns to about 4.5 microns with a standard geometric deviation of less than or equal to approximately 1.8 microns, and a mass median aerodynamic diameter of from about 2.8 microns to about 4.3 microns with a standard geometric deviation less than or equal to about 2 microns. In some embodiments, the aerosol can be produced using a vibrating mesh nebulizer. An example of a vibrating mesh nebulizer includes the PARI E-FLOW® nebulizer. More examples of nebulizers are provided
<td colspan="2">in US Patents</td><td colspan="3">Nos. 4,268,460; 4,253,468; 4,046,146;</td>
<td> 3,826,255;</td><td> 4,649,911;</td><td> 4,510,929;</td><td> 4,624,251;</td><td> 5,164,740;</td>
<td> 5,586,550;</td><td> 5,758,637;</td><td> 6,644,304;</td><td> 6,338,443;</td><td> 5,906,202;</td>
<td> 5,934,272;</td><td> 5,960,792;</td><td> 5,971,951;</td><td> 6,070,575;</td><td> 6,192,876;</td>
<td> 6,230,706;</td><td> 6,349,719;</td><td> 6,367,470;</td><td> 6,543,442;</td><td> 6,584,971;</td>
<td> 6,601,581;</td><td> 4,263,907;</td><td> 5,709,202;</td><td> 5,823,179;</td><td> 6,192,876;</td>
- 46 6,644,304; 5,549,102; 6,083,922;
6,161,536;
IMPI ^
MEXICAN INSTITUTE
OE THE ROUND <sup>, Nr</sup>CT4> ^ ·
6,557,549; and 6,612,303, all of which are ~ ± iiCü'rpordTr ~ eiT- “± 8r present by reference in its entirety. More commercial examples of nebulizers that can be used with the formulation described herein include Respirgard 11®, Aeroneb®, Aeroneb® Pro, and Aeroneb® Go produced by Aerogen; AERx® and AERx Essence ™ produced by Aradigm; Porta-Neb®, Freeway Freedom ™, Sidestream, Ventstream and I-neb produced by Respironics, Inc .; and PARI LC-Plus®, PARI LC-Star®, produced by PARI GmbH. As a further non-limiting example, US Patent No. 6,196,219 by reference in its entirety.
The amount of levofloxacin or ofloxacin that can be administered (as a breathable dose, a nebulizer-loaded dose, and / or a deposited dose) can include at least about 20 mg, about 30 mg, about 40 mg, about 50 mg, about
<img file="MX353288B_D0060.tif" />
<img file="MX353288B_D0061.tif" />
<img file="MX353288B_D0062.tif" />
<img file="MX353288B_D0063.tif" />
<img file="MX353288B_D0064.tif" />
<img file="MX353288B_D0065.tif" />
approximately approximately
<td>approximately</td><td> 90</td><td>mg,</td><td>approximately</td><td> 100</td><td>mg,</td>
<td>approximately</td><td> 110</td><td>mg,</td><td>approximately</td><td> 120</td><td>mg,</td>
<td>approximately</td><td> 125</td><td>mg,</td><td>approximately</td><td> 130</td><td>mg,</td>
<td>approximately</td><td> 140</td><td>mg,</td><td>approximately</td><td> 150</td><td>mg,</td>
<td>approximately</td><td> 160</td><td>mg,</td><td>approximately</td><td> 170</td><td>mg,</td>
<td>approximately</td><td> 180</td><td>mg,</td><td>approximately</td><td> 190</td><td>mg,</td>
<td>approximately</td><td> 200</td><td>mg,</td><td>approximately</td><td> 210</td><td>mg,</td>
rmr.
<td></td><td colspan="3">- 47 - and TO. 1N5</td><td>MPh Tirare Mexicano!> T! .A IRÍW.W 'INDUSTRIAL</td><td>\ · '. r</td>
<td>approximately</td><td> 220</td><td>mg,</td><td>approximately</td><td> 230</td><td>mg,</td>
<td>approximately</td><td> 240</td><td>mg,</td><td>approximately</td><td> 250</td><td>mg,</td>
<td>approximately</td><td> 260</td><td>mg,</td><td>approximately</td><td> 270</td><td>mg,</td>
<td>approximately</td><td> 280</td><td>mg,</td><td>approximately</td><td> 290</td><td>mg,</td>
<td>approximately</td><td> 300</td><td>mg,</td><td>approximately</td><td> 310</td><td>mg,</td>
<td>approximately</td><td> 320</td><td>mg,</td><td>approximately</td><td> 330</td><td>mg,</td>
<td>approximately</td><td> 340</td><td>mg,</td><td>approximately</td><td> 350</td><td>mg,</td>
<td>approximately</td><td> 460</td><td>mg,</td><td>approximately</td><td> 470</td><td>mg,</td>
<td>approximately</td><td> 480</td><td>mg,</td><td>approximately</td><td> 490</td><td>mg,</td>
<td>approximately</td><td> 500</td><td>mg,</td><td>approximately</td><td> 510</td><td>mg,</td>
<td>approximately</td><td> 520</td><td>mg,</td><td>approximately</td><td> 530</td><td>mg,</td>
<td>approximately</td><td> 540</td><td>mg,</td><td>approximately</td><td> 550</td><td>mg,</td>
<td>approximately</td><td> 560</td><td>mg,</td><td>approximately</td><td> 570</td><td>mg,</td>
<td>approximately</td><td> 580</td><td>mg,</td><td>approximately</td><td> 590</td><td>mg,</td>
<td>approximately</td><td> 600</td><td>mg,</td><td>approximately</td><td> 610</td><td>mg,</td>
<td>approximately</td><td> 620</td><td>mg,</td><td>approximately</td><td> 630</td><td>mg,</td>
<td>approximately</td><td> 640</td><td>mg,</td><td>approximately</td><td> 650</td><td>mg,</td>
<td>approximately</td><td> 660</td><td>mg,</td><td>approximately</td><td> 670</td><td>mg,</td>
<td>approximately</td><td> 680</td><td>mg,</td><td>approximately</td><td> 690</td><td>mg,</td>
<td>approximately</td><td> 700</td><td>mg,</td><td>approximately</td><td> 710</td><td>mg,</td>
<td>approximately</td><td> 720</td><td>mg,</td><td>approximately</td><td> 730</td><td>mg,</td>
<td>approximately</td><td> 740</td><td>mg,</td><td>approximately</td><td> 750</td><td>mg,</td>
<td>approximately</td><td> 760</td><td>mg,</td><td>approximately</td><td> 770</td><td>mg,</td>
<td>approximately</td><td> 780</td><td>mg,</td><td>approximately</td><td>790 mg,</td><td>and</td>
<td>approximately</td><td>800 mg.</td><td></td><td></td><td></td><td></td>
<td></td><td> - 48 -</td><td>IMPI ^ MEXICAN INSTITUTE DF LA MOPIérap tV 'ΕΥ industrial</td>
<td>Aerosol can</td><td>manage</td><td>to — the — lungs _in</td>
<td>less than about</td><td>10 minutes,</td><td>about 5</td>
<td>minutes, approximately</td><td>4 minutes,</td><td>about 3</td>
<td>minutes, approximately</td><td>2 minutes and</td><td>about 1</td>
<td>minute.</td><td></td><td></td>
<td>Indications</td><td></td><td></td>
<td>The methods and</td><td>compositions</td><td>described in</td>
present can be used to treat infections and obstructive pulmonary disorders, eg cystic fibrosis. Some modalities include treating an infection that comprises one or more bacteria that may include
Presudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alkali and Pseudomonas putida,
Stenotrophomonas maltophilia,
Aeromonas hydrophi lia,
Escherichia col i,
Citrobacter freundii,
Salmonella typhymurium,
Salmonella typhi,
Salmonella paratyphi,
Salmonella enteritidis,
Shigella dysenteriae,
Shigella flexneri, Shigella sonnei,
Enterobacter Cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca,
Serratia marcescens, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis,
Bordetella pertussis, Bordetella parapertussis, Bordetella
MHTlITb MEXICANO.>: * · Dt LA PHOFlFDAf- <'
INDUSTRIAL
<img file="MX353288B_D0066.tif" />
bronchiseptica, parainfluenzae,
Haemophilus
Haemophilus influenzae,
Haemophilus parahaemolyticus, haemolyticus,
Haemophilus
Haemophilus ducreyi
Oasteurella multocida,
Pasteurella haemolytica, Helicobacter pylori, Campylobacter your faith, Campylobacter jejuni, Campylobacter col i, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Burkholderia cepacia, Francisella tularensis, Kingella and Moraxella. In some modalities, the lung infection may include a gram negative anaerobic bacteria. In more previous modalities, the lung infection may include one or more of the bacteria selected from the group consisting of Bacteroides fragilis, Bacteroides distasonis, the Bacteroides homology group
3452Ά, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii and Bacteroides splanchnicus. In some modalities, the lung infection may include a gram positive bacteria. In some modalities, the lung infection may include one or more of the bacteria selected from the group consisting of
Coryn eba ct eri um diphtheriae,
Coryn eba ct eri um ulcerans,
Streptococcus pneumoniae,
Streptococcus agalactiae,
Streptococcus pyogenes,
Streptococcus milleri, Streptococcus (Group G), Streptococcus (Group C / F), Enterococcus faecalis, Enterococcus faecium
<img file="MX353288B_D0067.tif" />
Staphylococcus aureus,
Staphylococcus
IMPI
INSTITUTO MEXICANO BE LA ΗΟΙ · ΙΕΟΛΙ> INDUSTRIAL epidermidis,
Staphylococcus saprophyticus, Staphylococcus intermedius,
Staphylococcus hycus subsp.
Hycus,
Staphylococcus haemolyticus,
Staphylococcus hominis and
Staphylococcus saccharolyticus.
In some modalities, the lung infection may include a gram positive anaerobic bacteria.
In some modalities, the lung infection may include one or more bacteria selected from the group consisting of
Clostridium difficile, Clostridium perfringens, Clostridium tetini and Clostridium botulinum.
In some modalities, the lung infection may include acid-resistant bacteria.
In some modalities, the lung infection may include one or more bacteria selected from the group consisting of Mycobacterium tuberculosis,
Mycobacterium avium,
Mycobacterium intracellulare and
Mycobacterium leprae.
In some modalities, the lung infection may include an atypical bacteria. In some modalities, the lung infection may include one or more bacteria selected from the group consisting of Chlamydia pneumoniae and
Mycoplasma pneumoniae. In some modalities, the lung infection may comprise a gram-negative bacteria that does not ferment (NFGNB). Examples of NFGNB may include
Burkholeria spp., Stenotrophomonas spp., Acinetobacter spp., Pseudomonas spp., And Achromobacter spp.
More examples of useful bacteria in methods and
<td>compositions</td><td colspan="2">provided</td><td>in</td><td>the</td><td>D. '*. ; hi Si- ' Present</td><td>1 · '4 • JÍ'í ¿ML - · they can</td>
<td>Meet in</td><td>Bergey's</td><td>Handbook</td><td colspan="4">of Systematic Bacteriology</td>
<td colspan="2">(Bacteriology Manual</td><td colspan="2">systematic</td><td>of</td><td colspan="2">Bergey), Editor at</td>
<td>boss: Garríty,</td><td>George M.</td><td>Boone,</td><td>David</td><td>R;</td><td>Castenholz</td><td>Richard</td>
W. (Eds.) Originally published by Williams & Wilkins, 1984, 2<sup>to</sup> edition (2001), incorporated by reference in its entirety.
Some methods and compositions provided herein may be especially appropriate for the treatment of lung infections and disorders including microbial strains that may be difficult to treat using an antimicrobial agent delivered parenterally due to the need for high levels of parenteral dose, which may cause undesirable side effects, or due to a lack of any clinically effective antimicrobial agent. For example, administration of an aerosolized fluoroquinolone antimicrobial directly to the site of infection can reduce systemic exposure and can maximize the amount of the antimicrobial agent at the site of microbial infection. Such methods may be appropriate to treat infections involving microbes that are susceptible to fluoroquinolone antimicrobials as a way to reduce the frequency of selection of resistant microbes.
In some embodiments, the antimicrobial agent of
ΙΜΡΙΈ ^ iNSTrnrro mf.xicang tDtí & ífta
OF. THE F1ORIEDAD \
INLH'STUIAL ·· «—i-fluoroquinolone aerosol formulated with bivalent or trivalent cations is administered at a level sufficient to overcome emergency resistance in bacteria or to increase destruction efficiency such that resistance has no chance of developing .
Some embodiments of the methods and compositions described herein include achieving a reduction in a lung infection. The reduction in a lung infection can be measured using a variety of different methods. For example, in a lung infection comprising one or more organisms, a reduction in the density of the organism can be measured. In some modalities, treatment can achieve a reduction in the density of an organism by at least about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about
35%, about 40%, about 45%, about 50%, about 55%, about
60%, about 65%, about 70%, about 75%, about 80%, about
85%, about 90%, about 95%, and about 100%. In some modalities, treatment can achieve a reduction in the density of an organism by at least about 85%, about 86%, about 87%, about 88%, about about 92%, about
89%, approximately
94%, approximately
95%, about 97%,
99%, and approximately
The density shows taken from bronchial alveolar, the density of a
ΙΜΡΙ @ ^
MEXICAN INSTITUTE
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OF THE RROPIEOAO. , INDUSTRY!
approximately approximately approximately 98%,
100%.
from an organism can a subject, by sputum and serum.
organism can
Approximately 96% measured in one example of a wash
In some modalities, reduce by at least about 0.1, about 0.2, about
0.3, about 0.4, about 0.5, about 0.6, about 0.7, about
0.8, about 1.0, about 1.1, about 1.2, about 1.3, about
1.4, about 1.5, about 1.6, about 1.7, about 1.8, about
1.9, approximately 2.0, approximately 2.1, approximately 2.2, approximately 2.3, approximately 2.4, approximately 2.5 log CFU / g in sputum, or more.
Some embodiments of the methods and compositions described herein may include achieving an improvement in a parameter of lung function. Examples of such parameters may include FEV (forced expiration volume), FEV<sub>X</sub> (volume of forced expiration in 12 seconds), and fef 25-75 (forced expiration flow 25 to 75%). In
<img file="MX353288B_D0068.tif" />
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<img file="MX353288B_D0069.tif" />
In some modalities, the FEVi of a subject can be increased using the methods and compositions described herein, by at least about 1%, 2%, 3%, 4%, 5%,
6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22% , 23%, 24%, 25% and more. In some modalities, the FEVi of a subject can be increased using the methods and compositions described herein, by at least about 0.01 L, 0.02 L, 0.03 L, 0.04 L, and 0.05L and by at least about 0.1 L, 0.2 L , 0.3 L, 0.4 L, 0.5 L, 0.6 L, 0.7 L, 0.8 L, 0.9 L, 1.0 L and more.
In some embodiments, a subject's FEF 25-75 can be increased using the methods and compositions described herein, by at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8 %, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25% and more. In some embodiments, a subject's FEF 25-75 can be increased using the methods and compositions described herein, by at least about 0.01
<td>L, 0.02 L, 0.03 L, 0.04</td><td>L, and</td><td>0.05L</td><td>and for at least</td>
<td>about 0.1L, 0.2L,</td><td>0.3 L,</td><td>0.4 L,</td><td>0.5 L, 0.6 L, 0.7</td>
<td>L, 0.8 L, 0.9 L, 1.0 L and more.</td><td></td><td></td><td></td>
<td>Some modalities</td><td>the</td><td>methods</td><td>and compositions</td>
described herein may include reducing a subject's need for other inhaled or systemic antibiotics,
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<img file="MX353288B_D0070.tif" />
such as anti-pseudomonas antimicrobials. Such a reduction can be measured by a variety of methods, for example, by increasing the amount of inhaled or systemic antibiotics over time.
need can be measured by a the need of others
The reduction in such a variety of statistical means. For example, risk ratios can be used in a survival analysis. In some modalities, the risk ratio is lower to approximately 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1 and less.
Some modalities of the methods and compositions described herein may include decreasing the frequency of exacerbations, the severity of exacerbations, the duration of exacerbations, or the likelihood of an exacerbation occurring. An exacerbation can be defined by any of several methods and criteria provided by such methods. In some modalities, a patient may concurrently meet at least 4 symptoms / signs of the Fuchs definition of an exacerbation (Fuchs HJ, et al., Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis (Effect of recombinant human DNase aerosol on exacerbations of respiratory symptoms on lung function in patients with cystic fibrosis) N Engl J Med
<img file="MX353288B_D0071.tif" />
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1994: 331: 637-642, incorporated by reference in its entirety). Symptoms / signs defined by the Fuchs criterion include: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; discomfort, fatigue, or lethargy; temperature above 38 ° C; anorexia or weight loss; pain or tenderness in the sinuses; change in discharge from the sinuses; change in physical examination of the chest; decrease in lung function by 10% or more from the previously recorded value; and radiographic changes indicative of lung infection.
In some modalities, a patient with an increased exacerbation profile may have at least 1, at least 2, at least 3, and at least 4 of the following signs / symptoms, where the changes may be relative to the typical patient experience, for example, the daily experience and the weekly experience.
(1) Change in sputum, eg, for sputum production: patients have no change, slightly less or much less amounts of sputum when coughing, or for change in appearance of sputum: for sputum thickness , patients have thin or very thick sputum; for sputum color, patients have a better sputum color (better increases from brown -> green> yellow -> transparent).
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<img file="MX353288B_D0072.tif" />
(2) Hemoptysis, eg, patients have little or a large decrease in the amount of blood when coughing.
(3) Cough, eg, for the intensity of the cough, patients have mild or very light coughs; For the frequency of frequently coughing, patients cough slightly less or much less frequently.
Dyspnoea,
eg, for dyspnea on exertion, patients breathe a little more easily or much more easily while performing their daily activities.
(5) Discomfort, fatigue or lethargy,
eg, patients have a little more energy or much more energy in their daily activities,
eg, they climb stairs, a little more easily or much more easily.
(6) Temperature, eg, patients have a healthy normal temperature, eg, from about 37 ° C or patients do not have a recent history of fever.
(7) Anorexia or weight loss, eg, patients have no change in weight, or a slight increase in weight, and / or patients have little increase in appetite.
(8) Sinus pain or tenderness, eg, the patient has no sinus pain or tenderness or has less sinus pain or tenderness.
* ·. α ίϊ rss · »(9)
Change in
PREVENT Mexican ινητππό>, -ú
DELA EEOPIEDAD
INDUSTRIAL sinus discharge,
eg, patients have better sinus discharge (decreased thickness and / or better color).
(10) Change in physical examination of the chest, eg, patients have improved signs when examining their chest and may report, for example, a small decrease in chest congestion, or a large decrease in chest congestion.
(11) Lung function by 10% or more from a previously recorded value, eg, patients have improved lung function on lung function tests.
(12) Radiographic changes indicative of lung infection, eg, patients show improved radiographic changes indicating reduced lung infection.
In some modalities, exercise tolerance and / or absenteeism from scheduled events, eg, at school or work, can be measured as signs / symptoms of exacerbations.
Table 1 summarizes a variety of useful methods for measuring exacerbations.
<img file="MX353288B_D0073.tif" />
<img file="MX353288B_D0074.tif" />
TABLE 1
<td rowspan="2">Sign / symptom</td><td colspan="3"></td><td colspan="4">Method / Protocol</td>
<td>Fuchs</td><td>Ramsey</td><td>CFF</td><td>Rosenfeld (Seattle)<sup>TO</sup></td><td>Kraynack</td><td>Rabin</td><td>Blummer</td>
<td>Cough</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td>
<td>Sputum</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td>
<td>Haemoptysis</td><td>X</td><td></td><td></td><td></td><td>X</td><td>X</td><td></td>
<td>Dyspnoea</td><td>X</td><td></td><td></td><td></td><td>X</td><td></td><td>X</td>
<td>Exercise tolerance</td><td></td><td></td><td>X</td><td>X</td><td>X</td><td></td><td>X</td>
<td>Absenteeism</td><td></td><td>X</td><td>X</td><td>X</td><td>X</td><td></td><td></td>
<td>Fatigue</td><td>X</td><td></td><td></td><td></td><td>X</td><td></td><td>X</td>
<td>Fever</td><td>X</td><td>X</td><td>X</td><td></td><td>X</td><td></td><td></td>
<td>Decreased / loss of appetite</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td>
<td>Sinus pain</td><td>X</td><td>X</td><td></td><td></td><td></td><td></td><td></td>
<td>Sinus discharge</td><td>X</td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>Chest exam</td><td>X</td><td></td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td>
<td>Tachypnea</td><td></td><td>X</td><td>X</td><td></td><td></td><td></td><td>X</td>
<td>Pulmonary function</td><td>X</td><td>X</td><td>X</td><td>(X)</td><td>X</td><td>X</td><td>X</td>
<td>CXR</td><td>X</td><td></td><td>X</td><td></td><td>X</td><td></td><td>X</td>
<td>SaO2</td><td></td><td></td><td>X</td><td></td><td>X</td><td></td><td></td>
<td>Neutrophil</td><td></td><td>X</td><td></td><td></td><td></td><td></td><td></td>
<td>Criterion</td><td>4/12 more antibiotics</td><td>2/5 more 1/3</td><td> 3/11</td><td>Punctuation</td><td>Punctuation</td><td> 3/4</td><td> 3/4</td>
A: Rosenfeld M et al., Defining a pulmonary exacerbation in cystic fibrosis J. of Pediatrics 139: 359-365 (2001), incorporated by reference in its entirety.
B: Kraynack NC et al., Improving care at cystic fibrosis centers through quality improvement, Semin Respir Crit Care Med 2009 Oct 30 (5): 547-58), incorporated by reference in its entirety.
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<img file="MX353288B_D0075.tif" />
Some modalities of any of the foregoing methods include administering levofloxacin or ofloxacin in combination with a bivalent or trivalent cation in a quantity of doses, a schedule of administration and / or a method of administration sufficient to achieve the stated results .
Pediatric Patient Populations
Some embodiments provided herein relate to the use of the compositions provided herein to treat cystic fibrosis in a human. In some modalities, the human is a pediatric patient. In some modalities, the human age is younger up to approximately 18 years, younger up to approximately 17 years old, younger up to approximately 16 years old, younger up to approximately 15 years old, younger up to approximately 14 years old, younger up to approximately 13 years old, younger up to approximately 12 years old. , minor until approximately 11 years, minor until approximately 10 years, minor until approximately 9 years, minor until approximately 8 years, minor until approximately 7 years, minor to approximately 6 years, minor to approximately 5 years, minor to approximately 4 years, minor to approximately 3 years, minor to approximately 2 years and minor to approximately 1 year.
The doses of the therapeutic agents in aerosol
<img file="MX353288B_D0076.tif" />
<img file="MX353288B_D0077.tif" />
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<img file="MX353288B_D0078.tif" />
for pediatric subjects they may be less than _____ las-do-S-ia.-.
for an adult subject. In some embodiments, the dose can be determined, in part, due to a subject's weight.
For example, a subject that weighs from about 14 kg to about kg can receive a dose from about 120 mg, a subject that weighs from about 22 kg to about kg can receive a dose from about 180 weight over from mg per dose and a subject having about 30 kg can receive a dose from about 240 mg . In some embodiments, the aerosol therapeutic agent can be administered daily or twice daily. In some embodiments, the therapeutic aerosol agent can be administered over a period of at least 1 day, 3 days, 5 days, 10 days, 15 days, 20 days, and 30 days. In some embodiments, the aerosol therapeutic agent can be administered for approximately 14 days. In particular embodiments, the aerosol therapeutic agent is administered daily for 14 days.
In some embodiments, the human has a body weight less than about 70 kg, less than about 60 kg, less than about 50 kg, less than about 40 kg, less than about 30 kg, less than about 20 kg, and less than about 10 kg
T flv
In some modalities, the human minor body surface area up to approximately 1.8 m<sup>2</sup>, less than about 1.6 m<sup>2</sup>, less than about 1.4 less than about
1.2 minor to approximately
1.0 m<sup>2</sup>, minor until approximately
0.8 m<sup>2</sup>, less than about 0.6 m<sup>2</sup>, and less until approximately
0.4 m<sup>2</sup>.
<td>In</td><td colspan="4">some modalities,</td><td colspan="2">treating one</td><td>of</td>
<td>the humans</td><td colspan="2">previous</td><td colspan="2">understands</td><td>achieve</td><td colspan="2">a serum AUC</td>
<td>normalized</td><td>by</td><td colspan="2">the dose of</td><td>to the</td><td>less</td><td>approximately</td><td> 5</td>
<td>(ng.h / L) / mg</td><td>by</td><td>dose,</td><td>of</td><td>to the</td><td>less</td><td>approximately</td><td> 10</td>
<td>(ng.h / L) / mg</td><td>by</td><td>dose,</td><td>of</td><td>to the</td><td>less</td><td>approximately</td><td> 20</td>
<td>(ng.h / L) / mg</td><td>by</td><td>dose,</td><td>of</td><td>to the</td><td>less</td><td>approximately</td><td> 40</td>
<td>(ng.h / L) / mg</td><td>by</td><td>dose,</td><td>of</td><td>to the</td><td>less</td><td>approximately</td><td> 60</td>
<td>(ng.h / L) / mg</td><td>by</td><td>dose,</td><td>of</td><td>to the</td><td>less</td><td>approximately</td><td> 80</td>
<td>(ng.h / L) / mg</td><td>by</td><td>dose,</td><td>and of</td><td>to the</td><td>less</td><td>approximately</td><td> 100</td>
per dose.
(ng.h / L) / mg
In some modalities, treating one of the above humans involves achieving a C<sub>max</sub> in serum normalized by the highest dose up to about pg / L / mg per administered dose, higher up to about pg / L / mg per administered dose, higher up to about pg / L / mg per administered dose, higher up to about pg / L / mg per dose administered, greater up to approximately
<img file="MX353288B_D0079.tif" />
pg / L / mg per administered dose, higher up to pg / L / mg per administered dose, higher up to pg / L / mg per administered dose, higher up to pg / L / mg per administered dose, higher up to pg / L / mg per dose
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INDUSTRIAL -Τ '· * approximately approximately approximately administered, greater to approximately pg / L / mg per administered dose, greater to approximately 11 pg / L / mg per administered dose, greater to approximately 12 pg / L / mg per administered dose, greater up to about 13 pg / L / mg per administered dose, higher up to about 14 pg / L / mg per administered dose, higher up to about 15 pg / L / mg per administered dose, and higher up to about 16 pg / L / mg per administered dose.
Some modalities of any of the above methods of treating the cited humans include administering levofloxacin or ofloxacin in combination with a bivalent or trivalent cation in a sufficient number of doses, a schedule of administration and / or a method of administration sufficient to achieve the cited results. .
EXAMPLES
Example 1 - Phase Ib clinical study with levofloxacin
A single, blinded, placebo-controlled, multicenter escalation study was conducted to assess the safety, tolerability, and pharmacokinetic (PK) profile of aerosolized levofloxacin
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administered to patients with stable CF. , ..... All patients had had a culture of sputum P. aeruginosa within the previous 24 months and at the exploration visit. The study drug was administered twice daily for up to 14 days in three aerosol doses using a PARI eFlow device. Breathable doses delivered (RDD) ranged from approximately 40 mg, 80 mg, and 120 mg per treatment, corresponding to loaded doses of 78 mg, 175 mg, and 260 mg, respectively. Therefore, the estimated total daily RDDs were 80 mg, 160 mg and 240 mg. Study drugs were administered at 30 mg / ml (for the 40 mg dose) or at 50 mg / ml (for the 80 mg and 120 mg doses). Table 2 shows the formulations of the study drugs.
TABLE 2
<td></td><td>30 mg / ml levofloxacin solution</td><td>50 mg / ml levofloxacin solution</td><td>Placebo</td>
<td>Levofloxacin, mg / ml (mM)</td><td> 30 (81.6)</td><td> 50(136)</td><td> 0</td>
<td>Magnesium, mg / ml (mM)</td><td> 1.5 (60)</td><td> 2.4(100)</td><td> 2.4 (100)</td>
<td>Chloride, mg / ml (mM)</td><td> 4.3 (120)</td><td> 7.1 (200)</td><td> 7.1 (200)</td>
<td>Lactose, mg / ml (mM)</td><td> 51.4(150)</td><td> 51.4(150)</td><td> 51.4(150)</td>
<td>PH</td><td> 6.3</td><td> 6.3</td><td> 6.5</td>
<td>Osmolality, mOsm / kg</td><td> 314</td><td> 400</td><td> 424</td>
All patients used at least 1 concomitant medication during the study. Medications
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<img file="MX353288B_D0081.tif" />
concomitant first dose of study drug regardless of medication start date.
Concomitant medications used by at least 20% of patients included salbutamol, dornase alfa, azithromycin, seretide, pancrelipase, adeks, hypertonic solutions, and nortase.
Efficacy results
Table 3 summarizes the results of lung function tests for measurements of
FEVi.
The greatest relative improvement in FEVi after and 14 days of dosing was observed in the RDD of
120 mg (260 mg loaded) of 1evofloxacin cohort, with an average improvement of 14.79% and
17.58%, respectively. An average improvement of 8.90% persisted during the two weeks until the follow-up visit.
Furthermore, there appeared to be a dose response in patients receiving levofloxacin with patients in the 80 mg and 120 mg dose groups having an improvement in FEV.<sub>lz </sub>while those in the 40 mg dose group did not. All 9 patients in the 120 mg dose group had a relative increase in FEVi, with 4 patients having at least a 20% increase.
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TABLE 3
<td></td><td colspan="2">Average change in FEV<sub>1</sub> (%</td><td colspan="2">) for each treatment group</td>
<td>Point of</td><td>Placebo</td><td>RDD 40 mg</td><td>RDD 80 mg</td><td>RDD of 120 mg</td>
<td>weather</td><td></td><td>levofloxacin</td><td>levofloxacin</td><td>levofloxacin</td>
<td>Day 7</td><td>n - 10</td><td>n = 10</td><td>n = 10</td><td>n = 9</td>
<td></td><td> 5.75</td><td> -0.75</td><td> 6.15</td><td> 10.20</td>
<td>Day 14</td><td>n = 8</td><td>n = 10</td><td>n = 10</td><td>n = 9</td>
<td></td><td> 1.20</td><td> -1.55</td><td> 2.95</td><td> 16.90</td>
Table 4 shows the relative changes from baseline across visits (Day 1, 2, 7, 14, and 21) on pulmonary function tests for FEVi. In Table 3, the relative change from the baseline (CBG) was calculated as 'Result' FEVi minus 'Baseline' FEVi divided by 'Baseline' FEVi.
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TABLE 4
<td></td><td colspan="4">FEVf (L) for each Treatment Group</td>
<td>Time point</td><td>Placebo N = 10</td><td>Levofloxacin 40 mg RDD N = 10</td><td>Levofloxacin 80 mg RDD N = 10</td><td>Levofloxacin 120 mg RDD N = 10</td>
<td>Day 1 pre-dose (baseline)</td><td></td><td></td><td></td><td></td>
<td>n</td><td> 10</td><td> 10</td><td> 10</td><td> 10</td>
<td>average (SD)</td><td> 2.62 (1.150)</td><td> 2.26 (0.534)</td><td> 2.06 (0.649)</td><td> 2.56(1.121)</td>
<td>means, medium</td><td> 2.46</td><td> 2.30</td><td> 1.95</td><td> 2.23</td>
<td>Min MAX</td><td> 1.31,4.90</td><td> 1.58, 3.50</td><td> 1.17, 3.19</td><td> 1.43, 4.71</td>
<td>Day 2 pre-dose result</td><td></td><td></td><td></td><td></td>
<td>n</td><td> 10</td><td> 10</td><td> 10</td><td> 10</td>
<td>Average (SD)</td><td> 2.75(1.310)</td><td> 2.31 (0.594)</td><td> 2.10(0.709)</td><td> 2.73(1.132)</td>
<td>means, medium</td><td> 2.43</td><td> 2.32</td><td> 2.00</td><td> 2.38</td>
<td>Min MAX</td><td> 1.33, 5.50</td><td> 1.57, 3.60</td><td> 1.13, 3.46</td><td> 1.40, 4.72</td>
<td>Day 2 Relative CFB (%)</td><td></td><td></td><td></td><td></td>
<td>n</td><td> 10</td><td> 10</td><td> 10</td><td> 10</td>
<td>Average (SD)</td><td> 3.85 (6.627)</td><td> 1.92(8.315)</td><td> 1.57 (5.149)</td><td> 7.29(10.081</td>
<td>means, medium</td><td> 2.00</td><td> -0-30</td><td> 1.90</td><td> 6.60</td>
<td>Min MAX</td><td> -7.10, 12.20</td><td> -6.30, 21.70</td><td> -7.60, 8.90</td><td> -4.70, 23.90</td>
<td>Day 7 Result</td><td></td><td></td><td></td><td></td>
<td>n</td><td> 10</td><td> 10</td><td> 10</td><td> 9</td>
<td>Average (SD)</td><td> 2.82(1.361)</td><td> 2.30 (0.544)</td><td> 2.26(0.831)</td><td> 3.07 (1.220)</td>
<td>means, medium</td><td> 2.35</td><td> 2.30</td><td> 2.08</td><td> 2.40</td>
<td>Min MAX</td><td> 1.39, 5.20</td><td> 1.49, 3.48</td><td> 1.20, 3.79</td><td> 1.79, 4.99</td>
<td>Day 7 relative CFB (%)</td><td></td><td></td><td></td><td></td>
<td>n</td><td> 10</td><td> 10</td><td> 10</td><td> 9</td>
<td>Average (SD)</td><td> 5.86(10.196)</td><td> 1.60 (6.985)</td><td> 9.42 (18.911)</td><td> 14.79(12.865)</td>
<td>means, medium</td><td> 5.75</td><td> -0.75</td><td> 6.15</td><td> 10.20</td>
<td>Min MAX</td><td> -6.50, 29.40</td><td> -5.70, 17.90</td><td> -7.40, 59.90</td><td> 3.40, 37.70</td>
<img file="MX353288B_D0083.tif" />
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<td></td><td colspan="4">FEV <ÍL) face each Treatment Group</td>
<td>Time point</td><td>Placebo N = 10</td><td>Levofloxaclna 40 mg RDD N = 10</td><td>Levofloxacin 80 mg RDD N = 10</td><td>Levofloxacin 120 mg RDD N = 10</td>
<td>Day 14 pre-dose result</td><td></td><td></td><td></td><td></td>
<td>n</td><td> 8</td><td> 10</td><td> 10</td><td> 9</td>
<td>Average (SD)</td><td> 2.99 (1.272)</td><td> 2.26 (0.524)</td><td> 2.09 (0.616)</td><td> 3.12(1.173)</td>
<td>means, medium</td><td> 3.11</td><td> 2.30</td><td> 2.10</td><td> 2.57</td>
<td>Min MAX</td><td> 1.47, 5.20</td><td> 1.55, 3.38</td><td> 1.19, 3.21</td><td> 1.74, 4.78</td>
<td>Day14CFB relative (%)</td><td></td><td></td><td></td><td></td>
<td>n</td><td> 8</td><td> 10</td><td> 10</td><td> 9</td>
<td>Average (SD)</td><td> 2.00 (5.529)</td><td> 0.21 (8.440)</td><td> 2.69(10.125)</td><td> 17.58(15.089)</td>
<td>means, medium</td><td> 1.20</td><td> -1.55</td><td> 2.95</td><td> 16.90</td>
<td>Min MAX</td><td> -6.70, 8.80</td><td> -8.70, 23.10</td><td> -19.40, 19.10</td><td> 1.50, 41.50</td>
<td>Day 21 / result ET</td><td></td><td></td><td></td><td></td>
<td>n</td><td> 10</td><td> 10</td><td> 10</td><td> 10</td>
<td>Average (SD)</td><td> 2.75 (1.327)</td><td> 2.16(0.517)</td><td> 2.03 (0.532)</td><td> 2.75(1.155)</td>
<td>means, medium</td><td> 2.28</td><td> 2.07</td><td> 2.04</td><td> 2.48</td>
<td>Min MAX</td><td> 1.17, 5.10</td><td> 1.46, 3.42</td><td> 1.06, 2.82</td><td> 1.49, 4.87</td>
<td>Day 21 / CFB relative ET (%)</td><td></td><td></td><td></td><td></td>
<td>n</td><td> 10</td><td> 10</td><td> 10</td><td> 10</td>
<td>Average (SD)</td><td> 3.20(10.157)</td><td> -4.25 (7.092)</td><td> -1.03 (8.880)</td><td> 8.90(15.789)</td>
<td>means, medium</td><td> 1.75</td><td> -5.80</td><td> -3.10</td><td> 10.10</td>
<td>Min MAX</td><td> -10.70, 20.60</td><td> -12.70, 11.80</td><td> -11.60, 12.90</td><td> -15.90, 38.70</td>
<td colspan="5">ET = premature termination</td>
Colony-forming units of P.
aeruginosa on Day 1 were compared with colony forming units on Day 7 and 14. Table 5 summarizes the 'ΓΛ * ί' i., ·
X iV.L .¿.
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<img file="MX353288B_D0084.tif" />
percentage change of P.
aeruginosa in sputum (log CFU / g) in treatment groups. Declines were observed in P.
aeruginosa in sputum during all dosing days.
TABLE 5
<td rowspan="2">Time point</td><td colspan="2">Mean change in P. aeruginosa in sputum (log CFU / g) for the treatment group</td>
<td>placebo</td><td>Levofloxacin solution</td>
<td>Day 7</td><td>0.04 (n = 9)</td><td>-0.50 (n = 21)</td>
<td>Day 14</td><td>0.04 (n = 9)</td><td>-1.23 (n = 21)</td>
Security results
No serious adverse events related to the study drug were reported. Most adverse events were mild or moderate in severity and self-limiting. Most adverse events were mild, with complaints of aftertaste, cough, and migraine as the most commonly observed adverse events. No patient receiving levofloxacin inhalation solution met the criteria for drug intolerance. Adverse events reported in more than 1 patient receiving levofloxacin included abdominal pain, cough, disease progression (acute exacerbation), dysgeusia (bad taste), hemoptysis, migraine, nasal congestion, nasopharyngeal pain (sore throat), tract congestion respiratory and whistling. Table 6 summarizes the observed adverse events.
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<img file="MX353288B_D0085.tif" />
For in more than one CF patient who received levofloxacin.
Consequently, these results demonstrated the safety and tolerability of levofloxacin with multiple doses over days.
TABLE 6
<td rowspan="2">Adverse event</td><td colspan="4">Treatment group</td>
<td>Levofloxacin 40 mg (N = 10)</td><td>80 mg levofloxacin (N = 10)</td><td>120 mg levofloxacin (N = 10)</td><td>Placeb (N = 10)</td>
<td>Abdominal pain</td><td> 1 (10%)</td><td> -</td><td> 1 (10%)</td><td> --</td>
<td>Alopecia</td><td> --</td><td> 1 (10%)</td><td> -</td><td></td>
<td>Blood blister</td><td> -</td><td> -</td><td> 1 (10%)</td><td> —</td>
<td>Abnormal sounds when breathing</td><td></td><td></td><td> 1 (10%)</td><td></td>
<td>Chest discomfort</td><td></td><td> 1 (10%)</td><td></td><td> 1 (10%)</td>
<td>Cough</td><td> -</td><td> 4 (40%)</td><td> 4 (40%)</td><td> 1 (10%)</td>
<td>Diarrhea</td><td> 1 (10%)</td><td> -</td><td> -</td><td> -</td>
<td>Disease progression</td><td></td><td></td><td> 2 (20%)</td><td> 1 (10%)</td>
<td>Salivation</td><td></td><td> 1 (10%)</td><td></td><td></td>
<td>Dysgeusia</td><td> 3 (30%)</td><td> 6 (60%)</td><td> 5 (50%)</td><td> 1 (10%)</td>
<td>Dyspnoea</td><td> 1 (10%)</td><td> —</td><td></td><td> --</td>
<td>Fatigue</td><td> --</td><td> 1 (10%)</td><td> —</td><td> —</td>
<td>Side pain</td><td> 1 (10%)</td><td> -</td><td> —</td><td> --</td>
<td>Decreased forced expiration volume</td><td></td><td> 1 (10%)</td><td></td><td> 1 (10%)</td>
<td>Haemoptysis</td><td> --</td><td> 1 (10%)</td><td> 1 (10%)</td><td> —</td>
<td>Headache</td><td> --</td><td> 2 (20%)</td><td> 2 (20%)</td><td></td>
<td>Migraine</td><td> --</td><td> 1 (10%)</td><td> —</td><td> —</td>
<td>Nasal congestion</td><td> -</td><td> 1 (10%)</td><td> 1 (10%)</td><td></td>
<td>Non-cardiac pain in the chest</td><td></td><td> 1 (10%)</td><td></td><td></td>
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<td rowspan="2">Adverse event</td><td colspan="4">Treatment group</td>
<td>Levofloxacin 40 mg (N = 10)</td><td>80 mg levofloxacin (N = 10)</td><td>120 mg levofloxacin (N = 10)</td><td>Placebo "(N = 10)</td>
<td>Oral yeast infection</td><td> -</td><td> 1 (10%)</td><td> -</td><td> --</td>
<td>Oral paraetesia</td><td></td><td></td><td> 1 (10%)</td><td> —</td>
<td>Pain pharynx-larynx</td><td></td><td></td><td> 2 (20%)</td><td></td>
<td>Decreased lung function test</td><td></td><td></td><td> 1 (10%)</td><td></td>
<td>Pyrexia</td><td> -</td><td> -</td><td> 1 (10%)</td><td> —</td>
<td>Atoso erythem rash</td><td></td><td></td><td> 1 (10%)</td><td></td>
<td>Respiratory tract congestion</td><td></td><td></td><td> 2 (20%)</td><td></td>
<td>Sickness</td><td> --</td><td> 1 (10%)</td><td> -</td><td> --</td>
<td>Rhinorrhea</td><td> --</td><td> 1 (10%)</td><td> --</td><td> -</td>
<td>Thirst</td><td> --</td><td> 1 (10%)</td><td> --</td><td> -</td>
<td>Upper respiratory tract infection</td><td> 1 (10%)</td><td></td><td></td><td> 1 (10%)</td>
<td>Whistle</td><td> 1 (10%)</td><td></td><td> 1 (10%)</td><td> --</td>
Example 2 - Phase 2 clinical study with levofloxacin
A multicenter, randomized, double-blind, placebo-controlled phase 2 study was conducted to assess the safety, tolerability, and efficacy of three-dose regimens of levofloxacin formulated with MgCl<sub>2 </sub>administered for 28 days to stable CF patients. The following dose regimens (as nebulizer-loaded doses) were evaluated: 120 mg QS (daily); 240 mg QD
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Mexican INSTITUTE DF LA PS: 'PIEDAD INDUSTRIAL (daily; and 240 mg BID (twice a day). Based on characterization studies of the 100 mg / ml formulation formulation, these loaded doses of 120 and 240 mg correspond to the estimated respirable delivered doses (RDDs) using a PARI eFlow nebulizer from approximately 65 and 130 mg, respectively.<sub>max</sub> and plasma AUC of levofloxacin at all dose regimens selected for this study should provide concentrations in lung tissues that exceed those associated with bactericidal activity against CF pathogens (data not shown).
The formulation of the levofloxacin solution and the placebo are shown in Table 7. The study drug was administered by aerosol using the PARI eFlow® device with a mesh to deliver a particle size smaller than about 3.5 pm to 4.0 pm .
<img file="MX353288B_D0086.tif" />
TABLE 7
<td></td><td>Levofloxacin</td><td>Placebo</td>
<td>Levofloxacin, mg / ml (mM)</td><td> 100 (272)</td><td> 0</td>
<td>Mg, mg / ml (mM)</td><td> 5.0 (200)</td><td> 0</td>
<td>Cl, mg / ml (mM)</td><td> 14.4 (400)</td><td> 0</td>
<td>pH</td><td> 5-7</td><td> 6-8</td>
<td>Osmolality, mOsm / kg</td><td> 350 - 500</td><td> 300 - 500</td>
<td>Saline</td><td> -</td><td> 0.9%</td>
The patient's inclusion criteria included: (1) at least 16 years of age; (2) clinically diagnos
<img file="MX353288B_D0087.tif" />
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CF; (3) capable of emitting a 25% FEB1 but 85% of the predicted value in the exploration; (4) received at least 3 courses of inhaled antimicrobials during the preceding 12 months and had received at least 1 course of inhaled tobramycin (TOBI®) / colistin in the 2 months prior to Visit 1 (Day 1), but none in the 28 days prior to Visit 1 (Day 1); (5) had a sputum specimen on examination positive for P. aeruginosa and a history of at least 1 positive, positive sputum culture for P. aeruginosa within the past 18 months; and (6) clinically stable with no significant changes in health status within the past 30 days.
Patient exclusion criteria included: (1) the use of an investigational agent within 3 0 days prior to Visit 1 (Day 1); (2) the use of any nebulized or systemic antibiotic active against P. aeruginosa within 2 8 days prior to Visit 1 (Day 1), other than maintenance oral azithromycin, which must have been started at least 30 days before Visit 1 (Day 1); (3) hypersensitivity to fluoroquinolones or levofloxacin excipients formulated with MgC12; (4) intolerance to bronchodilators or unwilling to use a bronchodilator during the study; (5) the use of oral corticosteroids in doses exceeding the mg equivalent the
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<img file="MX353288B_D0088.tif" />
treatment of CF (eg, or elimination of 10 mg prednisone / day or 20 days; (6) changes in technique or within 14 days prior to changes in the introductory medical regimen, dose escalation, such as dornase alfa, non-spheroidal anti-inflammatory agents, azithromycin, hypertonic saline, or inhaled corticosteroids) within 30 days of Visit 1 (Day 1); (8) history of lung transplantation; (9) evidence of acute upper respiratory tract infection within 10 days or lower respiratory tract infection within 30 days prior to Visit 1 (Day 1);
(10) pregnancy, lactation, or unwilling to practice birth control or withdrawal while participating in the study (women only); (11) history of seizures or low seizure threshold (eg, epilepsy); (12) renal dysfunction (calculated creatinine clearance [CrCl] <50 ml / min) on examination; (13) aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin x the upper limit of normal (ULN) upon examination or evidence of severe liver disease (eg, cirrhosis, portal hypertension); (14) history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection / seropositivity; (15) history of hemoptysis 30 ml during any 24-hour period during the 30 days prior to visit 1;
(16) saturation
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15% relative decline in FEVi (L) from examination to Visit 1 (Day 1).
Patients were evaluated on Day 1, 7, 14, and 28, and then up to 28 days after completing the study drug, ie, Days 42 and 56. The study drug formulation, ie, levofloxacin, was shows on the
Table 7. The end of the study was defined as the last visit of the last patient. Study populations included: (1) safety / modified attempt to treat (MITT) population that included all patients enrolled in the study who received at least one dose of study drug; (2) evaluable efficacy (EE) population that included all patients enrolled in the study without major protocol violations who received at least 80% of the study drug doses during the 28 days of study drug therapy; and (3) a pharmacokinetic (PK) population that included all patients who received at least one dose of the study drug and from whom at least one PK blood sample was collected.
Approximately 32 patients per treatment stage provided 80% of the potential to detect the difference between treatment arms using a bilateral covariance analysis (ANCOVA), with 5% alpha,
<img file="MX353288B_D0089.tif" />
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<img file="MX353288B_D0090.tif" />
assuming a standard deviation (SD) of 1.5 and a mean change in log CFU in P. aeruginosa of 0.75 decrease,
O. 75 decrease, no change and 0.24 increase for 240 mg levofloxacin twice daily, 240 mg levofloxacin daily, 12 0 mg levof loxacin daily, and placebo treatment arms, respectively. Sample size calculations assumed a 10% discontinuation rate from the study; consequently, patients who discontinued the study were not replaced.
Efficacy was assessed by microbiological evaluation of sputum samples, time of need for anti-pseudomonal antimicrobials, revised cystic fibrosis questionnaire (CFQ-R), and lung function tests. Additionally, a primary efficacy comparison tested H<sub>or</sub>: the average decline in the log CFUs of
P. aeruginosa from the start of administration of levofloxacin or placebo (Day 1) until four weeks later is the same for all four groups, against Ηχ: the average decline in log CFUs is different for at least one of the four groups using a repeated measures mixed effects model that fits for the minimum inhibitory concentration of levofloxacin at baseline (MIC) as a continuous variable (log base 2 transformed), a lung function from the baseline, and a geographic region (US versus ex US).
Pairwise comparisons were conducted as secondary analyzes.
<img file="MX353288B_D0091.tif" />
í 'all branches of treatment
Efficacy endpoints including clinical endpoints, pulmonary function tests, and additional microbiological parameters were assessed as changes from Day 1 until subsequent visits where endpoint data was collected. The time to need intravenous / oral / inhaled anti-pseudomonas antimicrobials was assessed from Day 1 until the final visit using survival analysis.
The primary population for efficacy analysis was the EE population, but efficacy endpoints were also analyzed using the MITT population.
The patients enrolled in the study had an average of 5 courses of aerosol antibiotics during the previous 12 months. The baseline FEV1 (as predicted percentage) was 53% across the entire study and was not different between groups. The baseline mean MICs of all Pseudomonas aeruginosa isolates recovered from all patients (n = 592) for levofloxacin was 4 mg / L and the MIC90 was 16, also similar across all groups. These MICs are indicative of baseline non-susceptibility / resistance to levofloxacin, as defined by the reference methods.
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Concomitant medication used by patients during the study included dornase alfa, azithromycin, salbutamol, pancrelipase, hypertonic sodium chloride, seretide, and ADEK, and are summarized for the EE population in Table 8. Table 9 summarizes the patient's disposition in the study. The results of the study shown were the statistically significant advantages of aerosolized levofloxacin compared to placebo in various clinical and microbiological measurements, despite the use of concomitant medications, resistance to levofloxacin, and previous use of other aerosolized antibiotics, including tobramycin and colistin.
TABLE 8
<td>Medication</td><td>Placebo (N = 37)</td><td>120 mg levofloxacin QD (N = 38)</td><td>240 mg levofloxacin QD (N = 37)</td><td>240 mg levofloxacin IDB (N = 39)</td><td>Such (N = 1519</td>
<td>Dornasa alfa</td><td> 31 (83.8%)</td><td> 27 (71.1%)</td><td> 33 (89.2%)</td><td> 29 (74.4%)</td><td> 120 (79.5%)</td>
<td>Azithromycin</td><td> 25 (67.6%)</td><td> 29 (76.3%)</td><td> 26 (70.3%)</td><td> 32 (82.1%)</td><td> 112(74.2%)</td>
<td>Salbutamol</td><td> 25 (67.6%)</td><td> 29 (76.3%)</td><td> 25 (67.6%)</td><td> 23 (59.0%)</td><td> 102 (67.5%)</td>
<td>Pancrelipase</td><td> 19(51.4%)</td><td> 21 (55.3%)</td><td> 22 (59.5%)</td><td> 21 (53.8%)</td><td> 83 (55.0%)</td>
<td>Sodium chloride</td><td> 22 (59.5%)</td><td> 13(34.2%)</td><td> 13(35.1%)</td><td> 22 (56.4%)</td><td> 70 (46.4%)</td>
<td>Seretida</td><td> 19(51.4%)</td><td> 20 (52.6%)</td><td> 16(43.2%)</td><td> 15(38.5%)</td><td> 70 (46.4%)</td>
<td>ADEK</td><td> 10(27.0%)</td><td> 13(34.2%)</td><td> 10(27.0%)</td><td> 13(33.3%)</td><td> 46 (30.5%)</td>
<img file="MX353288B_D0092.tif" />
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TABLE 9
<img file="MX353288B_D0093.tif" />
<td colspan="2">Provision</td><td>Placebo</td><td>120 mg of levofloxacin QD</td><td>240 mg levofloxacin QD</td><td>240 mg levofloxacin IDB</td><td>total</td>
<td colspan="2">Enrolled patients</td><td> 37</td><td> 38</td><td> 37</td><td> 39</td><td> 151</td>
<td colspan="2">Security Population / MITT</td><td> 37 (100.0%)</td><td> 38 (100.0%)</td><td> 37 (100.0%)</td><td> 39 (100.0%)</td><td> 151 (100.0%)</td>
<td colspan="2">Evaluable efficacy population</td><td> 32 (86.5%)</td><td> 35(92.1%)</td><td> 35 (94.6%)</td><td> 34 (87.2%)</td><td> 136 (90.1%)</td>
<td colspan="2">PK population</td><td> 37 (100.0%)</td><td> 37 (97.4%)</td><td> 37 (100.0%)</td><td> 39 (100.0%)</td><td> 150 (99.3%)</td>
<td colspan="2">Study completed</td><td> 35 (94.6%)</td><td> 37 (97.4%)</td><td> 35 (94.6%)</td><td> 36 (92.3%)</td><td> 143 (94.7%)</td>
<td colspan="2">Discontinued from study</td><td> 2 (5.4%)</td><td> 1 (2.6%)</td><td> 2 (5.4%)</td><td> 3 (7.7%)</td><td> 8 (5.3%)</td>
<td rowspan="4">Main reason for discontinuation of study</td><td>Adverse event</td><td> 2 5.4%)</td><td> 1 (2.6%)</td><td> 1 (2.7%)</td><td> 2(5.1%)</td><td> 6 (4.0%)</td>
<td>Withdrawal of consent</td><td> 0 (0.0%)</td><td> 0 (0.0%)</td><td> 1 (2.7%)</td><td> 0 (0.0%)</td><td> 1 (0.7%)</td>
<td>Other</td><td> 0 (0.0%)</td><td> 0 (0.0%)</td><td> 0 (0.0%)</td><td> 1 (2.6%)</td><td> 1 (0.7%)</td>
<td>Main reason for discontinuing the study<sup>3</sup></td><td> 5(13.5%)</td><td> 3 (7.9%)</td><td> 1 (2.7%)</td><td> 2(5.1%)</td><td> 11 (7.3%)</td>
<td rowspan="2"></td><td>Adverse event</td><td> 4(10.8%)</td><td> 3 (7.9%)</td><td> 1 (2.7%)</td><td> 2(5.1%)</td><td> 10 (6.6%)</td>
<td>Other</td><td> 1 (2.7%)</td><td> 0 (0.0%)</td><td> 0 (0.0%)</td><td> 0 (0.0%)</td><td> 1 (0.7%)</td>
a: Patients could be included in both study discontinuation and study drug categories.
Microbial evaluations
Changes in P. aeruginosa density (log CFU / g in sputum) for sputum samples taken from EE and poblaciones populations are summarized in Tables 10 and 11, respectively (SD = standard deviation). Changes in MIC for P. aeruginosa density (log CFU / g in
Mexican INSTITUTE '' fC-O't-— Ή ia property K- ~ bOUSTRlAl sputum) to levof loxacin (all -ai £ aam ^ mn.q) for populations of EE and MITT are shown in Tables 12 and 13 respectively . Furthermore, changes in the highest MIC values for P. aeruginosa isolates to levofloxacin were determined for EE and MITT populations and are summarized in Tables 14 and 15, respectively. Tables 16 and 17 summarize the percentage of the EE and MITT populations, respectively, with categorical changes in the highest MIC values for P. aeruginosa isolates to levofloxacin. Tables 18 and 19 summarize the changes in the density of non-fermenting gram negative bacilli (NFGNB), excluding P. aeruginosa, only with patients with positive NFGNB counts at baseline, for EE and MITT populations, respectively. Tables 2 0 and 21 summarize the changes for putative S. aureus density (log CFU / g in sputum) only for patients with positive S. aureus counts at baseline, for EE and MITT populations, respectively.
<img file="MX353288B_D0094.tif" />
<img file="MX353288B_D0095.tif" />
TABLE 10
<td colspan="2" rowspan="2"></td><td colspan="5">EE population - P. aeruginosa density (log ™ CFU / g in sputum)</td>
<td>Placebo (N = 32)</td><td>129 mg levofloxacin QD (N = 35)</td><td>240 mg levofloxacin QD (N = 35)</td><td>240 mg levofloxacin IDB (N = 34)</td><td>240 mg of levofloxacin combined QD and IDB (N = 69)</td>
<td rowspan="2">Day 1</td><td>Average (SD)</td><td> 7.49 (1.674)</td><td> 7.43(1.622)</td><td> 7.16(1.597)</td><td> 7.26(1.433)</td><td> 7.21 (1.508)</td>
<td>half</td><td> 8.11</td><td> 8.17</td><td> 7.97</td><td> 7.84</td><td> 7.90</td>
<td rowspan="2">Day 7</td><td>Average (SD)</td><td> 7.37 (1.746)</td><td> 6.64(1.818)</td><td> 6.94(1.783)</td><td> 6.23(1.850)</td><td> 6.59(1.838)</td>
<td>Half</td><td> 8.14</td><td> 6.86</td><td> 7.15</td><td> 6.52</td><td> 6.77</td>
<td rowspan="3">Change from baseline to day 7</td><td>Average (SD)</td><td> -0.12 (1.422)</td><td> -0.76(1.263)</td><td> -0.25 (1.789)</td><td> -1.03 (1.921)</td><td> -0.64 (1.883)</td>
<td>Half</td><td> 0.09</td><td> -0.58</td><td> -0.18</td><td> -0.88</td><td> -0.37</td>
<td>P value</td><td></td><td> 0.0277</td><td> 0.5892</td><td> 0.0051</td><td> 0.0533</td>
<td rowspan="2">Day 14</td><td>Average (SD)</td><td> 7.48 (1.616)</td><td> 7.32(1.643)</td><td> 6.69 (1.628)</td><td> 6.43 (1.725)</td><td> 6.56(1.669)</td>
<td>Half</td><td> 7.85</td><td> 8.00</td><td> 6.46</td><td> 6.81</td><td> 6.78</td>
<td rowspan="3">Change from baseline to day 14</td><td>Average (SD)</td><td> 0.03 (1.355)</td><td> -0.10(1.240)</td><td> -0.47 (1.905)</td><td> -0.83(1.901)</td><td> -0.65 (1.898)</td>
<td>Half - 0.01</td><td> -0.01</td><td> 0.00</td><td> -0.11</td><td> -0.91</td><td> -0.46</td>
<td>P value</td><td></td><td> 0.3929</td><td> 0.0998</td><td> 0.0047</td><td> 0.0105</td>
<td rowspan="2">Day 28</td><td>Average (SD)</td><td> 7.85 (1.050)</td><td> 7.25 (1.431)</td><td> 6.78 (1.896)</td><td> 6.65(1.440)</td><td> 6.72 (1.683)</td>
<td>Half</td><td> 8.28</td><td> 7.78</td><td> 7.38</td><td> 6.40</td><td> 6.90</td>
<td rowspan="3">Change from baseline day 28</td><td>Average (SD)</td><td> 0.36 (1.329)</td><td> -0.31 (1.050)</td><td> -0.38(1.780)</td><td> -0.74 (1.488)</td><td> -0.55 (1.645)</td>
<td>Half</td><td> 0.00</td><td> -0.20</td><td> -0.52</td><td> -0.68</td><td> -0.58</td>
<td>P value</td><td></td><td> 0.0093</td><td> 0.0075</td><td> 0.0002</td><td> 0.0002</td>
TABLE 11
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<img file="MX353288B_D0096.tif" />
<td colspan="2" rowspan="2"></td><td colspan="5">MITT population - density of P. aeruginosa (log<sub>10</sub> CFU / g in sputum)</td>
<td>Placebo (N = 37)</td><td>129 mg levofloxacin QD (N = 38)</td><td>240 mg levofloxacin QD (N = 37)</td><td>240 mg levofloxacin IDB (N = 39)</td><td>240 mg levofloxacin combined QD and IDB (N = 76)</td>
<td rowspan="2">Day 1</td><td>Average (SD)</td><td> 7.45 (1.656)</td><td> 7.43(1.571)</td><td> 7.08 (1.742)</td><td> 7.17(1.726)</td><td> 7.12(1.723)</td>
<td>half</td><td> 8.10</td><td> 8.16</td><td> 7.97</td><td> 7.90</td><td> 7.91</td>
<td rowspan="2">Day 7</td><td>Average (SD)</td><td> 7.21 (1.750)</td><td> 6.68(1.778)</td><td> 6.79 (1.854)</td><td> 6.16(1.969)</td><td> 6.47(1.927)</td>
<td>Half</td><td> 7.97</td><td> 6.98</td><td> 6.95</td><td> 6.53</td><td> 6.69</td>
<td rowspan="3">Change from baseline to day 7</td><td>Average (SD)</td><td> -0.24 (1.429)</td><td> -0.70(1.257)</td><td> -0.31 (1.823)</td><td> -0.97 (1.846)</td><td> -0.65 (1.852)</td>
<td>Half</td><td> 0.00</td><td> -0.53</td><td> -0.18</td><td> -0.76</td><td> -0.35</td>
<td>P value</td><td></td><td> 0.1091</td><td> 0.6986</td><td> 0.0124</td><td> 0.0956</td>
<td rowspan="2">Day 14</td><td>Average (SD)</td><td> 7.33 (1.651)</td><td> 7.33(1.602)</td><td> 6.63(1.744)</td><td> 6.32 (1.875)</td><td> 6.48(1.806)</td>
<td>Half</td><td> 7.85</td><td> 8.00</td><td> 6.46</td><td> 6.70</td><td> 6.61</td>
<td rowspan="3">Change from baseline to day 14</td><td>Average (SD)</td><td> -0.07 (1.373)</td><td> -0.07 (1.213)</td><td> -0.44 (1.855)</td><td> -0.81 (1.838)</td><td> -0.63 (1.843)</td>
<td>Half - 0.01</td><td> -0.02</td><td> 0.00</td><td> -0.10</td><td> -0.79</td><td> -0.40</td>
<td>P value</td><td></td><td> 0.7941</td><td> 0.1972</td><td> 0.0091</td><td> 0.0251</td>
<td rowspan="2">Day 28</td><td>Average (SD)</td><td> 7.66 (1.236)</td><td> 7.26(1.394)</td><td> 6.82 (1.869)</td><td> 6.58(1.704)</td><td> 6.70(1.781)</td>
<td>Half</td><td> 8.26</td><td> 7.78</td><td> 7.38</td><td> 6.48</td><td> 6.90</td>
<td rowspan="3">Change from baseline to day 28</td><td>Average (SD)</td><td> 0.21 (1-377)</td><td> -0.27 (1.035)</td><td> -0.25 (1.857)</td><td> -0.66 (1.422)</td><td> -0.46 (1.658)</td>
<td>Half</td><td> 0.00</td><td> -0.20</td><td> -0.39</td><td> -0.56</td><td> -0.52</td>
<td>P value</td><td></td><td> 0.0728</td><td> 0.0698</td><td> 0.0014</td><td> 0.0039</td>
TABLE 12
<img file="MX353288B_D0097.tif" />
MFX'CAN INSTITUTE OF THE INDUSTRIAL ERUHEUAU
<td colspan="2" rowspan="2"></td><td colspan="5">EE - MIC population of P. aeruginosa to levofloxacin (all organisms) (pg / ml)</td>
<td>Placebo</td><td>Levofloxacin QD 120</td><td>240 mg levofloxacin QD</td><td>240 mg levofloxacin IDB</td><td>240 mg levofloxacin combined QD and IDB</td>
<td rowspan="4">Day one</td><td>N</td><td> 124</td><td> 140</td><td> 140</td><td> 136</td><td> 276</td>
<td>Average (SD)</td><td> 6.0 (5.00)</td><td> 11.5 (21.98)</td><td> 6.3 (8.85)</td><td> 6.8 (8.80)</td><td> 6.5 (8.82)</td>
<td>MICso</td><td> 4</td><td> 4</td><td> 4</td><td> 4</td><td> 4</td>
<td>MICgo</td><td> 16</td><td> 32</td><td> 16</td><td> 16</td><td> 16</td>
<td rowspan="5">Day 7</td><td>N</td><td> 124</td><td> 136</td><td> 132</td><td> 132</td><td> 264</td>
<td>Average (SD)</td><td> 6.6 (6.73)</td><td> 9.9(17.28)</td><td> 6.8(16.13)</td><td> 8.8(17.28)</td><td> 7.8(16.71)</td>
<td>Min, max</td><td> 0.25, 32</td><td> 0.13, 128</td><td> 0.13, 128</td><td> 0.13,128</td><td> 0.13,128</td>
<td>MIC50</td><td> 4</td><td> 4</td><td> 2</td><td> 4</td><td> 4</td>
<td>MICgo</td><td> 8</td><td> 16</td><td> 16</td><td> 16</td><td> 16</td>
<td rowspan="4">Day 14</td><td>N</td><td> 120</td><td> 140</td><td> 136</td><td> 132</td><td> 268</td>
<td>Average (SD)</td><td> 5.6 (6.79)</td><td> 13.0 (29.34)</td><td> 6.6 (9.44)</td><td> 8.4(14.47)</td><td> 7.5 (12.19)</td>
<td>MIC50</td><td> 4</td><td> 4</td><td> 4</td><td> 4</td><td> 4</td>
<td>MICgo</td><td> 8</td><td> 32</td><td> 16</td><td> 16</td><td> 16</td>
<td rowspan="4">Day 28</td><td>N</td><td> 128</td><td> 132</td><td> 136</td><td> 124</td><td> 260</td>
<td>Average (SD)</td><td> 5.0 (3.97)</td><td> 8.9(13.47)</td><td> 6.0 (7.57)</td><td> 10.1 (16.32)</td><td> 8.0(12.67)</td>
<td>MICso</td><td> 4</td><td> 4</td><td> 4</td><td> 4</td><td> 4</td>
<td>MICgo</td><td> 8</td><td> 16</td><td> 16</td><td> 32</td><td> 16</td>
IMPI
MEXICAN INSTITUTE
OF THE INDUSTRIAL PRDPIECxn
TABLE 13
<img file="MX353288B_D0098.tif" />
<td colspan="2" rowspan="2"></td><td colspan="5">MITT - MIC population of P. aeruginosa to levofloxacin (all organisms) (pg / ml)</td>
<td>Placebo</td><td>Levofloxacin QD 120</td><td>240 mg levofloxacin QD</td><td>240 mg levofloxacin IDB</td><td>240 mg of levofloxacin combined QD and IDB</td>
<td rowspan="4">Day 1</td><td>N</td><td> 140</td><td> 152</td><td> 148</td><td> 152</td><td> 300</td>
<td>Average (SD)</td><td> 6.1 (5.40)</td><td> 11.0 (21.17)</td><td> 6.1 (8.54)</td><td> 6.8 (8.47)</td><td> 6.4 (8.55)</td>
<td>MICso</td><td> 4</td><td> 4</td><td> 4</td><td> 4</td><td> 4</td>
<td>MICgo</td><td> 16</td><td> 32</td><td> 16</td><td> 16</td><td> 16</td>
<td rowspan="4">Day 7</td><td>N</td><td> 136</td><td> 144</td><td> 140</td><td> 140</td><td> 280</td>
<td>Average (SD)</td><td> 6.8 (7.33)</td><td> 9.6(16.83)</td><td> 6.7(15.69)</td><td> 8.6(16.82)</td><td> 7.6(16.27)</td>
<td>MICso</td><td> 4</td><td> 4</td><td> 2</td><td> 4</td><td> 4</td>
<td>MICgo</td><td> 16</td><td> 16</td><td> 16</td><td> 16</td><td> 16</td>
<td rowspan="4">Day 14</td><td>N</td><td> 128</td><td> 144</td><td> 144</td><td> 140</td><td> 284</td>
<td>Average (SD)</td><td> 5.8 (7.09)</td><td> 12.9 (28.95)</td><td> 6.5 (9.23)</td><td> 8.2(14.11)</td><td> 7.3(11.90)</td>
<td>MICso</td><td> 4</td><td> 6</td><td> 4</td><td> 4</td><td> 4</td>
<td>MIC90</td><td> 16</td><td> 32</td><td> 16</td><td> 16</td><td> 16</td>
<td rowspan="4">Day 28</td><td>N</td><td> 132</td><td> 136</td><td> 140</td><td> 132</td><td> 272</td>
<td>Average (SD)</td><td> 4.9 (3.97)</td><td> 8.8(13.32)</td><td> 5.9 (7.50)</td><td> 9.9(15.98)</td><td> 7.9(12.51)</td>
<td>MICso</td><td> 4</td><td> 4</td><td> 4</td><td> 4</td><td> 4</td>
<td>MICgo</td><td> 8</td><td> 16</td><td> 16</td><td> 32</td><td> 16</td>
<img file="MX353288B_D0099.tif" />
<img file="MX353288B_D0100.tif" />
<img file="MX353288B_D0101.tif" />
TABLE 14
<td colspan="2" rowspan="2"></td><td colspan="5">Higher EE - MIC population from P. aeruginosa to levofloxacin (pg / ml)</td>
<td>Placebo (N = 32)</td><td>120 mg levofloxacin QD (N = 35)</td><td>240 mg levofloxacin QD (N = 35)</td><td>240 mg levofloxacin IDB (N = 34)</td><td>240 mg levofloxacin combined QD and IDB (N = 69)</td>
<td>Day 1</td><td>Average</td><td> 8.79(6.661)</td><td> 14.98 (22.383)</td><td> 9.35 (12.991)</td><td> 11.58 (13.399)</td><td> 10.45 (13.144)</td>
<td></td><td>(SD)</td><td></td><td></td><td></td><td></td><td></td>
<td></td><td>MICso</td><td> 8</td><td> 8</td><td> 4</td><td> 6</td><td> 4</td>
<td></td><td>MICgo</td><td> 16</td><td> 32</td><td> 32</td><td> 32</td><td> 32</td>
<td>Day 7</td><td>Average</td><td> 8.77 (7.455)</td><td> 15.71 (22.523)</td><td> 10.86(22.222)</td><td> 13.05 (22.838)</td><td> 11.95 (22.385)</td>
<td></td><td>(SD)</td><td></td><td></td><td></td><td></td><td></td>
<td></td><td>MICso</td><td> 8</td><td> 8</td><td> 4</td><td> 4</td><td> 4</td>
<td></td><td>MICgo</td><td> 16</td><td> 32</td><td> 16</td><td> 32</td><td> 32</td>
<td>Day</td><td>Average</td><td> 8.42</td><td> 21.16(43.639)</td><td> 9.56(12.409)</td><td> 15.18(25.541)</td><td> 12.33 (20.032)</td>
<td> 14</td><td>(SD)</td><td> (11.437)</td><td></td><td></td><td></td><td></td>
<td></td><td>MICso</td><td> 6</td><td> 8</td><td> 8</td><td> 4</td><td> 8</td>
<td></td><td>MICgo</td><td> 16</td><td> 32</td><td> 16</td><td> 32</td><td> 32</td>
<td>Day</td><td>Average</td><td> 7.32(4.961)</td><td> 12.91 (15.669)</td><td> 9.42(11.658)</td><td> 17.97 (26.008)</td><td> 13.56 (20.252)</td>
<td> 28</td><td>(SD)</td><td></td><td></td><td></td><td></td><td></td>
<td></td><td>MICso</td><td> 8</td><td> 8</td><td> 8</td><td> 8</td><td> 8</td>
<td></td><td>MICgo</td><td> 16</td><td> 32</td><td> 16</td><td> 32</td><td> 32</td>
<img file="MX353288B_D0102.tif" />
<img file="MX353288B_D0103.tif" />
TABLE 15
<td colspan="2" rowspan="2"></td><td colspan="5">MITT population - highest MIC of P. aeruginosa to levofloxacin (pg / ml)</td>
<td>Placebo (N = 37)</td><td>120 mg levofloxacin QD (N = 38)</td><td>240 mg levofloxacin QD (N = 37)</td><td>240 mg levofloxacin IDB (N = 39)</td><td>240 mg of levofloxacin combined QD and IDB (N = 76)</td>
<td>Day 1</td><td>Average</td><td> 9.04</td><td> 14.32(21.583)</td><td> 9.06(12.685)</td><td> 11.41 (12.816)</td><td> 10.25(12.720)</td>
<td></td><td>(SD)</td><td> (7.593)</td><td></td><td></td><td></td><td></td>
<td></td><td>MICso</td><td> 8</td><td> 8</td><td> 4</td><td> 6</td><td> 4</td>
<td></td><td>MICgo</td><td> 16</td><td> 32</td><td> 32</td><td> 32</td><td> 32</td>
<td>Day 7</td><td>Average</td><td> 9.06</td><td> 15.17(21.991)</td><td> 10.53 (21.615)</td><td> 12.96 (21.902)</td><td> 11.76 (21.639)</td>
<td></td><td>(SD)</td><td> (8.203)</td><td></td><td></td><td></td><td></td>
<td></td><td>MICso</td><td> 8</td><td> 8</td><td> 4</td><td> 6</td><td> 4</td>
<td></td><td>MICgo</td><td> 16</td><td> 32</td><td> 16</td><td> 32</td><td> 16</td>
<td>Day 14</td><td>Average</td><td> 8.78</td><td> 20.34 (42.555)</td><td> 9.28(12.136)</td><td> 14.86(24.522)</td><td> 12.07(19.415)</td>
<td></td><td>(SD)</td><td> (11.554)</td><td></td><td></td><td></td><td></td>
<td></td><td>MICso</td><td> 6</td><td> 8</td><td> 8</td><td> 6</td><td> 8</td>
<td></td><td>MICgo</td><td> 16</td><td> 32</td><td> 16</td><td> 32</td><td> 32</td>
<td>Day 28</td><td>Average</td><td> 7.78</td><td> 12.74(15.286)</td><td> 9.17(11.389)</td><td> 17.91 (25.067)</td><td> 13.48(19.734)</td>
<td></td><td>(SD)</td><td> (6.334)</td><td></td><td></td><td></td><td></td>
<td></td><td>MICso</td><td> 8</td><td> 8</td><td> 8</td><td> 8</td><td> 8</td>
<td></td><td>MICgo</td><td> 16</td><td> 32</td><td> 16</td><td> 32</td><td> 32</td>
IMPI
<img file="MX353288B_D0104.tif" />
- 87 TABLE 16
<td colspan="2" rowspan="2"></td><td colspan="5">EE population - categorical change in highest MIC from P. aeruginosa to levofloxacin (population%)</td>
<td>Placebo (N = 32)</td><td>120 mg levofloxacin QD (N = 35)</td><td>240 mg levofloxacin QD (N = 35)</td><td>240 mg levofloxacin IDB (N = 34)</td><td>240 mg of levofloxacin combined QD and IDB (N = 69)</td>
<td rowspan="2">Change from baseline to Day 7</td><td>Increment> = 4 times</td><td> 6.5%</td><td> 2.9%</td><td> 12.1%</td><td> 9.1%</td><td> 10.6%</td>
<td>Increment <4 times</td><td> 93.5%</td><td> 97.1%</td><td> 87.9%</td><td> 90.9%</td><td> 89.4%</td>
<td rowspan="2">Change from baseline to Day 14</td><td>Increment> = 4 times</td><td> 10.0%</td><td> 11.4%</td><td> 5.9%</td><td> 18.2%</td><td> 11.9%</td>
<td>Increment <4 times</td><td> 90.0%</td><td> 88.6%</td><td> 94.1%</td><td> 81.8%</td><td> 88.1%</td>
<td rowspan="2">Change from baseline to Day 28</td><td>Increment> = 4 times</td><td> 9.4%</td><td> 9.1%</td><td> 8.8%</td><td> 15.6%</td><td> 10.6%</td>
<td>Increment <4 times</td><td> 90.6%</td><td> 90.9%</td><td> 91.2%</td><td> 84.4%</td><td> 87.9%</td>
<td rowspan="2">Change from baseline to Day 56 / premature termination</td><td>Increment> = 4 times</td><td> 22.6%</td><td> 6.2%</td><td> 5.7%</td><td> 15.2%</td><td> 10.3%</td>
<td>Increment <4 times</td><td> 77.4%</td><td> 93.8%</td><td> 94.3%</td><td> 84.8%</td><td> 89.7%</td>
TABLE 17
<td colspan="2" rowspan="2"></td><td colspan="5">MITT population - categorical change in highest MIC d P. aeruginosa to levofloxacin (population%)</td>
<td>Placebo (N = 37)</td><td>120 mg levofloxacin QD (N = 38)</td><td>240 mg levofloxacin QD (N = 37)</td><td>240 mg levofloxacin IDB (N = 39)</td><td>240 mg of levofloxacin combined QD and IDB (N = 76)</td>
<td rowspan="2">Change from baseline to Day 7</td><td>Increment < 4 times</td><td> 5.7%</td><td> 2.8%</td><td> 11.4%</td><td> 8.3%</td><td> 9.9%</td>
<td>Increment < 4 times</td><td> 94.3%</td><td> 97.2%</td><td> 88.6%</td><td> 91.7%</td><td> 90.1%</td>
<td rowspan="2">Change from baseline to Day 14</td><td>Increment> = 4 times</td><td> 8.8%</td><td> 10.8%</td><td> 5.6%</td><td> 16.7%</td><td> 11.1%</td>
<td>Increment < 4 times</td><td> 91.2%</td><td> 89.2%</td><td> 94.4%</td><td> 83.3%</td><td> 88.9%</td>
<td rowspan="2">Change from baseline to Day 28</td><td>Increment> = 4 times</td><td> 8.3%</td><td> 8.6%</td><td> 8.3%</td><td> 14.3%</td><td> 11.3%</td>
<td>Increment < 4 times</td><td> 91.7%</td><td> 91.4%</td><td> 91.7%</td><td> 85.7%</td><td> 88.7%</td>
<td rowspan="2">Change from baseline to Day 56 / premature termination</td><td>Increment> = 4 times</td><td> 20.0%</td><td> 5.9%</td><td> 5.4%</td><td> 13.9%</td><td> 9.6%</td>
<td>Increment < 4 times</td><td> 80.0%</td><td> 94.1%</td><td> 94.6%</td><td> 86.1%</td><td> 90.4%</td>
<img file="MX353288B_D0105.tif" />
TABLE 18
IMPI • NSTmrro mwucano
Dt LA PROHÉDAt) INDUSTRIAL
<img file="MX353288B_D0106.tif" />
<td colspan="2" rowspan="2"></td><td colspan="6">Population EE - Change in density of gram negative bacilli that do not ferment (log<sub>10</sub> CFU / g is sputum</td>
<td>Placebo (N = 5)</td><td>120 mg of levofloxaclna QD (N = 5)</td><td>240 mg levofloxaclna QD (N = 5)</td><td>240 mg levofloxaclna IDB (N = 4)</td><td>240 mg levofloxacline combined QD and IDB (N = 9)</td><td>Levofloxaclna combined (N = 4)</td>
<td>Day 1</td><td>Average (SD)</td><td> 6.60 (1.113)</td><td> 5.69 (2.674)</td><td> 4.65 (2.271)</td><td> 5.52 (2.291)</td><td> 5.03(2.182)</td><td> 5.27 (2.288)</td>
<td>Day 7</td><td>Average (SD)</td><td> 6.26 (3.018)</td><td> 4.54(2.361)</td><td> 2.18(1.614)</td><td> 5.01 (3.068)</td><td> 3.44 (2.657)</td><td> 3.83 (2.522)</td>
<td rowspan="2">Change from baseline to Day 7</td><td>Average (SD)</td><td> -0.34 (2.610</td><td> -1.15 ()1.607</td><td> -2.47 (3.346)</td><td> -0.51 (3.184)</td><td> -1.60 (3.235)</td><td> -1.44 (2.699)</td>
<td>P value</td><td></td><td> 0.1206</td><td> 0.0476</td><td> 0.7552</td><td> 0.1755</td><td> 0.1178</td>
<td>Day 14</td><td>Average (SD)</td><td> 5.94 (3.002)</td><td> 3.15(3.122)</td><td> 2.04 (2.315)</td><td> 6.02(1.894)</td><td> 3.80 (2.903)</td><td> 3.57 (2.880)</td>
<td rowspan="2">Change from baseline to Day 14</td><td>Average (SD)</td><td> -0.66 (2.315)</td><td> -2.54 (3.057)</td><td> -2.61(3.222)</td><td> 0.50(1.638)</td><td> -1.23 (2.980)</td><td> -1.70 (2.961)</td>
<td>P value</td><td></td><td> 0.0894</td><td> 0.1571</td><td> 0.5983</td><td> 0.5932</td><td> 0.2824</td>
<td>Day 28</td><td>Average (SD)</td><td> 5.60 (3.012)</td><td> 5.10(2.938)</td><td> 1.36 (0.808)</td><td> 5.01 (2.758)</td><td> 2.98 (2.621)</td><td> 3.63 (2.787)</td>
<td rowspan="2">Change from baseline to Day 28</td><td>Average (SD)</td><td> -1.00 (3.262)</td><td> -1.44 (4.739)</td><td> -3.29(2.401)</td><td> -0.51 (1.438)</td><td> -2.05 (2.407)</td><td> -1.87 (3.092)</td>
<td>P value</td><td></td><td> 0.2997</td><td> 0.0479</td><td> 0.9881</td><td> 0.2237</td><td> 0.1956</td>
IMPI
<img file="MX353288B_D0107.tif" />
TABLE 19
<td colspan="2" rowspan="2"></td><td colspan="6">MITT population - Change in density of non-fermenting gram n gative bacilli (log<sub>10</sub> CFU / g in sputum</td>
<td>Placebo (N = 6)</td><td>120 mg of levofloxacin QD (N = 5)</td><td>240 mg levofloxacin QD (N = 7)</td><td>240 mg levofloxacin IDB (N = 5)</td><td>240 mg levofloxacin combined QD and BID (N = 12)</td><td>Levofloxacin combined (N = 17)</td>
<td>Day 1</td><td>Average (SD)</td><td> 5.88 (2.018)</td><td> 5.69 (2.674)</td><td> 5.26 (2.203)</td><td> 6.05(2.317)</td><td> 5.59 (2.184)</td><td> 5.62 (2.251)</td>
<td>Day 7</td><td>Average (SD)</td><td> 5.44 (3.375)</td><td> 4.54 (2.361)</td><td> 2.52 (1.997)</td><td> 5.63 (3.004)</td><td> 3.82 (2.832)</td><td> 4.03 (2.650)</td>
<td rowspan="2">Change from baseline on Day 7</td><td>Average (SD)</td><td> -0.45 (2.350)</td><td> -1.15 (1.607)</td><td> -2.73 (2.882)</td><td> -0.42 (2.765)</td><td> -1.77 (2.955)</td><td> -1.59 (2.594)</td>
<td>P value</td><td></td><td> 0.2680</td><td> 0.0485</td><td> 0.6562</td><td> 0.3749</td><td> 0.2748</td>
<td>Day 14</td><td>Average (SD)</td><td> 5.17 (3.286)</td><td> 3.15(3.122)</td><td> 3.08 (2.599)</td><td> 6.50(1.964)</td><td> 4.50 (2.862)</td><td> 4.11 (2.911)</td>
<td rowspan="2">Change from baseline to Day 14</td><td>Average (SD)</td><td> -0.72 (2.075)</td><td> -2.54 (3.057)</td><td> -2.18 (2.784)</td><td> 0.45(1.423)</td><td> -1.08 (2.605)</td><td> -1.51 (2.733)</td>
<td>P value</td><td></td><td> 0.1020</td><td> 0.1924</td><td> 0.2832</td><td> 0.9333</td><td> 0.4410</td>
<td>Day 28</td><td>Average (SD)</td><td> 4.88 (3.215)</td><td> 5.10(2.938)</td><td> 2.77 (2.505)</td><td> 5.63 (2.762)</td><td> 3.96 (2.892)</td><td> 4.24 (2.850)</td>
<td rowspan="2">Change from baseline to Day 28</td><td>Average (SD)</td><td> -1.00 (2.917)</td><td> -1.44 (4.739)</td><td> -2.49 (2.538)</td><td> -0.43 (1.260)</td><td> -1.63 (2.284)</td><td> -1.58 (2.885)</td>
<td>P value</td><td></td><td> 0.5733</td><td> 0.1606</td><td> 0.4532</td><td> 0.7286</td><td> 0.6211</td>
- -f
<img file="MX353288B_D0108.tif" />
MEXICAN INSTITUTE
OF THE ΡΚϋ.ΊΕΠΑΙ · INVUSTMAL
<img file="MX353288B_D0109.tif" />
TABLE 20
<td colspan="2" rowspan="2"></td><td colspan="6">Population EE - Change in density of S. aureus pr suntiva (log<sub>10</sub> CFU / g in sputum</td>
<td>Placebo (N = 16)</td><td>120 mg of levofloxacin QD (N = 16)</td><td>240 mg levofloxacin QD (N = 19)</td><td>240 mg levofloxacin IDB (N = 13)</td><td>240 mg levofloxacin combined QD and BID (N = 32)</td><td>Levofloxacin combined (N = 48)</td>
<td>Day 1</td><td>Average (SD)</td><td> 5.67 (2.125)</td><td> 5.72(1.871)</td><td> 5.64(1.985)</td><td> 5.68 (2.196)</td><td> 5.65 (2.038)</td><td> 5.68 (1.964)</td>
<td>Day 7</td><td>Average (SD)</td><td> 5.53 (2.152)</td><td> 4.53 (2.272)</td><td> 5.34(2.321)</td><td> 4.96 (2.992)</td><td> 5.18(2.574)</td><td> 4.97 (2.473)</td>
<td rowspan="2">Change from baseline to Day 7</td><td>Average (SD)</td><td> -0.14 (0.968)</td><td> -1.19 (1.722)</td><td> -0.30 (1.579)</td><td> -0.72 (1.159)</td><td> -0.47 (1.419)</td><td> -0.71 (1.546)</td>
<td>P value</td><td></td><td> 0.0347</td><td> 0.5969</td><td> 0.2039</td><td> 0.2891</td><td> 0.1059</td>
<td>Day 14</td><td>Average (SD)</td><td> 5.35 (2.469)</td><td> 5.30 (2.543)</td><td> 5.14(2.594)</td><td> 4.70 (2.829)</td><td> 4.96 (2.656)</td><td> 5.08 (2.597)</td>
<td rowspan="2">Change from baseline to Day 14</td><td>Average (SD)</td><td> -0.32 (1.259)</td><td> -0.42 (1.273)</td><td> -0.50 (1.766)</td><td> -0.98 (0.998)</td><td> -0.69 (1.502)</td><td> -0.60 (1.422)</td>
<td>P value</td><td></td><td> 0.6684</td><td> 0.5883</td><td> 0.1593</td><td> 0.2497</td><td> 0.3259</td>
<td>Day 28</td><td>Average (SD)</td><td> 5.46 (2.647)</td><td> 5.31 (2.482)</td><td> 4.56 (2.724)</td><td> 5.42 (2.973)</td><td> 4.89 (2.806)</td><td> 5.04 (2.680)</td>
<td rowspan="2">Change from baseline to Day 28</td><td>Average (SD)</td><td> -0.21 (1-137)</td><td> -0.41 (1.146)</td><td> -1.08 (2.622)</td><td> -0.38 (1.144)</td><td> -0.81 (2.173)</td><td> -0.67 (1.882)</td>
<td>P value</td><td></td><td> 0.6124</td><td> 0.1186</td><td> 0.6403</td><td> 0.2589</td><td> 0.3159</td>
- 92 IMPI
<img file="MX353288B_D0110.tif" />
TABLE 21
<td colspan="2" rowspan="2"></td><td colspan="6">MITT Population - Presumptive change in density of S. aureus (log<sub>10</sub> CFU / g in sputum</td>
<td>Placebo (N = 19)</td><td>120 mg of levofloxacin QD (N = 17)</td><td>240 mg levofloxacin QD (N = 21)</td><td>240 mg levofloxacin IDB (N = 16)</td><td>240 mg levofloxacin combined QDyBID (N = 37)</td><td>Levofloxacin combined (N = 54)</td>
<td>Day 1</td><td>Average (SD)</td><td> 6.06 (2.152)</td><td> 5.89(1.941)</td><td> 5.63(1.894)</td><td> 5.51 (2.318)</td><td> 5.58 (2.058)</td><td> 5.68 (2.009)</td>
<td>Day 7</td><td>Average (SD)</td><td> 5.78 (2.071)</td><td> 4.75 (2.382)</td><td> 5.23 (2.249)</td><td> 4.65 (2.954)</td><td> 4.99 (2.543)</td><td> 4.91 (2.472)</td>
<td rowspan="2">Change from baseline on Day 7</td><td>Average (SD)</td><td> -0.28 (0.985)</td><td> -1.14 (1.681)</td><td> -0.40 (1.615)</td><td> -0.66 (1.243)</td><td> -0.51 (1.458)</td><td> -0.71 (1.545)</td>
<td>P value</td><td></td><td> 0.0563</td><td> 0.6856</td><td> 0.3058</td><td> 0.3995</td><td> 0.1653</td>
<td>Day 14</td><td>Average (SD)</td><td> 5.64 (2.387)</td><td> 5.48 (2.568)</td><td> 4.97 (2.579)</td><td> 4.32 (2.820)</td><td> 4.70 (2.662)</td><td> 4.95 (2.633)</td>
<td rowspan="2">Change from baseline to Day 14</td><td>Average (SD)</td><td> -0.42 (1.216)</td><td> -0.41 (1.233)</td><td> -0.66 (1.907)</td><td> -0.99 (0.981)</td><td> -0.80 (1.578)</td><td> -0.68 (1.475)</td>
<td>P value</td><td></td><td> 0.8238</td><td> 0.5691</td><td> 0.2231</td><td> 0.2939</td><td> 0.4058</td>
<td>Day 28</td><td>Average (SD)</td><td> 5.65 (2-511)</td><td> 5.49(2.510)</td><td> 4.48 (2.633)</td><td> 4.95 (3.018)</td><td> 4.66 (2.760)</td><td> 4.93 (2.684)</td>
<td rowspan="2">Change from baseline to Day 28</td><td>Average (SD)</td><td> -0.41 (1.240)</td><td> -041 (1.110)</td><td> -1.15 (2.578)</td><td> -0.44 (1.150)</td><td> -0.87 (2.131)</td><td> -0.72 (1.860)</td>
<td>P value</td><td></td><td> 0.8341</td><td> 0.1623</td><td> 0.7846</td><td> 0.3528</td><td> 0.4572</td>
The densities of P.
aeruginosa decreased from baseline values (Day 1) during the course of the
<img file="MX353288B_D0111.tif" />
study in all three levofloxacin treatment groups in both EE and
ΜΙΤΤ
Figures 3 and 4 show the mean changes in P. aeruginosa densities over time for each treatment group.
In the EE population, there was a decrease in the density of P. aeruginosa in patients who were administered 240 mg of levofloxacin twice daily from a mean value of 7.84 log CFU / g in sputum on Day 1 to a value 6.40 log CFU / g medium in sputum on Day 28, representing a reduction in the density of P. aeruginosa in sputum from approximately 96%. In patients who were administered 240 mg of levof loxacin daily, there was a decrease in the density of P. aeruginosa from a mean value of 7.97 log CFU / g in sputum on Day 1 to a mean value of 7.38 log CFU / g in sputum on Day 28, representing a reduction in the density of P. aeruginosa in sputum from approximately 74% . In patients who were administered 120 mg of levof loxacin daily, there was an increase in the density of P. aeruginosa from an average value of 8.17 log CFU / g in sputum on Day 1 to an average value of 7.78 log CFU / g in sputum on Day 28, representing a reduction in the density of P. aeruginosa in sputum from approximately 59% . The greatest differences for the density of P. aeruginosa in sputum between patients who received placebo and patients who received
- 94 IMPI
<img file="MX353288B_D0112.tif" />
those given levofloxacin were 1.62 log CFU / g in sputum on Day 7, 1.39 log CFU / g in sputum on Day
14, and 1.88 log CFU / g in sputum on Day 28.
In the MITT population, there was a decrease in the density of P. aeruginosa in patients administered 240 mg of levofloxacin twice daily from a mean value of 7.90 log CFU / g in sputum on Day 1 to a value mean of 6.48 log CFU / g in sputum on Day 28, representing a reduction in the density of P. aeruginosa in sputum from approximately 96%. In patients who were administered 240 mg of levofloxacin daily, there was a decrease in the density of P. aeruginosa from a mean value of 7.97 log CFU / g in sputum on Day 1 to a mean value of 7.38 log CFU / g in sputum on Day 28, representing a reduction in the density of P. aeruginosa in sputum from approximately 74% . In patients receiving 12 0 mg levof loxacin daily, there was an increase in the density of P. aeruginosa from a mean value of 8.16 log CFU / g in sputum on Day 1 to a mean value of 7.78 log CFU / g in sputum on Day 28, representing a reduction in the density of P. aeruginosa in sputum from approximately 58% . The greatest differences for the density of P. aeruginosa in sputum between the patients who received placebo and the patients who received levofloxacin were 1.44 log CFU / g in sputum on Day 7,
1.39 log CFU / g in
<img file="MX353288B_D0113.tif" />
[NST.Tt'TO MEXICANA DE LA PXOi'lSiJAD esputtfW<sup>1</sup>
14, and 1.7 8 log CFU / g in sputum on Day 28?
For the EE and MITT populations, the baseline MIC50 values for P. aeruginosa isolates from patients given placebo, 120 mg daily, 240 mg daily, and 240 mg twice daily were 8 pg / ml, 8, 4 pg / ml and 6 pg / ml, respectively. On Day 28, the MIC50 values for P. aeruginosa isolates from patients administered placebo, 120 mg daily, 240 mg daily, and
240 mg twice daily were 8 pg / ml, 8 pg / ml, 8 pg / ml and pg / ml, respectively. MIC90 values for isolates of
P. aeruginosa from patients given placebo, 120 mg daily, 240 mg daily, and
240 mg twice a pg / ml, pg / ml and 32 pg / ml, day were 16 pg / ml, 32
<td>respectively.</td><td>At</td><td>Day</td><td> 28,</td><td colspan="3">MIC values<sub>90</sub> for</td>
<td>P. isolates</td><td>aeruginous</td><td>of</td><td>the</td><td>patients</td><td>to those who</td><td>I know</td>
<td colspan="2">administered placebo, 120 mg</td><td>to the</td><td>day,</td><td>240 mg a</td><td>day, and 240</td><td>mg</td>
<td>twice daily</td><td>were from</td><td> 16</td><td>ug / ml.</td><td>32 pg / ml,</td><td>16 pg / ml and</td><td> 32</td>
pg / ml, respectively.
The similarity of MIC50 values
Corresponding MIC90 between the
Day 1 and Day 28 for the populations of
EE and MITT indicate that P. cultures
Aeruginosa patients did not develop any significant resistance to levofloxacin.
Clinical evaluations - CFQ-R questionnaire
IMPI
<img file="MX353288B_D0114.tif" />
Patients completed the CFQ-R questionnaire with domains that included: respiratory, body image.
digestion, appetite, emotion, health perception, physical, role / school, social, treatment burden, vitality and weight. Tables 22 and 23 summarize the results for the CFQ-R respiratory domain for EE and MITT populations, respectively. Table 24 summarizes the changes in score for various CFQ-R domains from baseline to Visit 4 in the MITT population.
TABLE 22
<td colspan="2" rowspan="2"></td><td colspan="5">EE population - CFQ-R respiratory domain</td>
<td>Placebo (N = 32)</td><td>120 mg levofloxacin QD (N = 35)</td><td>240 mg levofloxacin QD (N = 35)</td><td>240 mg levofloxacin IDB (N = 34)</td><td>240 mg levofloxacin combined QD and IDB (N = 69)</td>
<td rowspan="2">Day 1</td><td>Average (SD)</td><td> 66.7(14.39)</td><td> 63.5(15.84)</td><td> 60.8(15.83)</td><td> 60.3(16.42)</td><td> 60.5 (16.00)</td>
<td>Half</td><td> 66.7</td><td> 66.7</td><td> 61.1</td><td> 61.1</td><td> 61.1</td>
<td rowspan="2">Day 14</td><td>Average (SD)</td><td> 66.7(15.84)</td><td> 67.8(13.79)</td><td> 63.2 (19.34)</td><td> 68.8(19.15)</td><td> 66.0(19.31)</td>
<td>Half</td><td> 63.9</td><td> 66.7</td><td> 66.7</td><td> 72.2</td><td> 66.7</td>
<td rowspan="3">Change from baseline to Day 14</td><td>Average (SD)</td><td> -0.0(11.20)</td><td> 4.3 (9.82)</td><td> 2.1 (16.41)</td><td> 8.5(15.55)</td><td> 5.3(16.19)</td>
<td>Half</td><td> 0.0</td><td> 5.5</td><td> 0.0</td><td> 5.6</td><td> 5.6</td>
<td>P value</td><td></td><td> 0.3953</td><td> 0.9534</td><td> 0.0374</td><td> 0.2171</td>
<td rowspan="2">Day 28</td><td>Average (SD)</td><td> 64.9(18.53)</td><td> 65.1 (17.28)</td><td> 61.7(19.37)</td><td> 66.0 (19.68)</td><td> 63.8(19.49)</td>
<td>Half</td><td> 63.9</td><td> 66.7</td><td> 66.7</td><td> 72.2</td><td> 66.7</td>
<td rowspan="3">Change from baseline to Day 28</td><td>Average (SD)</td><td> -1.7(14.90)</td><td> 1.6 (12.32)</td><td> 1.0(14.91)</td><td> 5.2(17.56)</td><td> 3.0(16.27)</td>
<td>Half</td><td> 0.0</td><td> 0.0</td><td> 0.0</td><td> 5.5</td><td> 0.0</td>
<td>P value</td><td></td><td> 0.6183</td><td> 0.8145</td><td> 0.0924</td><td> 0.2690</td>
<img file="MX353288B_D0115.tif" />
industrial
<img file="MX353288B_D0116.tif" />
··? ·> Μ ·
TABLE 23
<td colspan="2" rowspan="2"></td><td colspan="5">MITT population - CFQ-R respiratory domain</td>
<td>Placebo (N = 37)</td><td>120 mg levofloxacin QD (N = 38)</td><td>240 mg levofloxacin QD (N = 37)</td><td>240 mg levofloxacin IDB (N = 39)</td><td>240 mg levofloxacin combined QD and IDB (N = 76)</td>
<td rowspan="2">Day 1</td><td>Average (SD)</td><td> 64.9 (14.17)</td><td> 62.3(15.88)</td><td> 61.3(15.52)</td><td> 60.5(16.31)</td><td> 60.9(15.83)</td>
<td>Half</td><td> 66.7</td><td> 61.1</td><td> 61.1</td><td> 61.1</td><td> 61.1</td>
<td rowspan="2">Day 14</td><td>Average (SD)</td><td> 64.6 (15.84)</td><td> 67.1 (13.70)</td><td> 63.0(19.74)</td><td> 68.4(19.51)</td><td> 65.8(19.68)</td>
<td>Half</td><td> 61.1</td><td> 66.7</td><td> 66.7</td><td> 72.2</td><td> 69.4</td>
<td rowspan="3">Change from baseline to Day 14</td><td>Average (SD)</td><td> -0.3 (10.79)</td><td> 4.5 (9.78)</td><td> 1.4(17.54)</td><td> 7.5(15.30)</td><td> 4.5(16.59)</td>
<td>Half</td><td> 0.0</td><td> 5.5</td><td> 0.0</td><td> 5.6</td><td> 5.5</td>
<td>P value</td><td></td><td> 0.2559</td><td> 0.8964</td><td> 0.0334</td><td> 0.1937</td>
<td rowspan="3">Day 28</td><td>Average (SW)</td><td> 63.1 (18.01)</td><td> 64.6(16.94)</td><td> 61.6(19.74)</td><td> 64.4 (20.39)</td><td> 63.0(19.98)</td>
<td>Half</td><td> 61.1</td><td> 66.7</td><td> 66.7</td><td> 72.2</td><td> 66.7</td>
<td>Min, max</td><td> 22.94</td><td> 17,100</td><td> 17,89</td><td> 22,94</td><td> 17,94</td>
<td rowspan="3">Change from baseline to Day 28</td><td>Average (SD)</td><td> -1.8 (14.11)</td><td> 2.0(12.23)</td><td> 0.3(16.14)</td><td> 3.0(19.18)</td><td> 1.7(17.66)</td>
<td>Half</td><td> 0.0</td><td> 0.0</td><td> 0.0</td><td> 5.5</td><td> 0.0</td>
<td>P value</td><td></td><td> 0.5029</td><td> 0.8365</td><td> 0.2174</td><td> 0.4069</td>
<img file="MX353288B_D0117.tif" />
<img file="MX353288B_D0118.tif" />
TABLE 24
<td rowspan="2">CFQ Scale- R</td><td colspan="2">LS mean change from baseline</td><td rowspan="2">Meda difference LS (95% Cl)</td><td rowspan="2">P value</td>
<td>Placebo (N = 37)</td><td>240 mg Levofloxacin BID (N = 39)</td>
<td>Respiratory</td><td> -0.44</td><td> 4.06</td><td> 4.50 (-2.68, 11.67)</td><td> 0.2174</td>
<td>Body image</td><td> .59</td><td> 0.34</td><td> -0.25 (-6.00, 5.50)</td><td> 0.9315</td>
<td>Digestion</td><td> -1.35</td><td> 1.11</td><td> 2.46 (-3.27, 8.18)</td><td> 0.3975</td>
<td>Appetite</td><td> -3.29</td><td> 2.41</td><td> 5.70 (0.78, 10.62)</td><td> 0.0235</td>
<td>Emotion</td><td> 2.32</td><td> 2.22</td><td> -0.09 (-4.34, 4.15)</td><td> 0.9651</td>
<td>Perception of</td><td> -2.1</td><td> 0.52</td><td> 2.58 (-3.70, 8.86)</td><td> 0.4177</td>
<td>Health</td><td></td><td></td><td></td><td></td>
<td>Physical</td><td> -2.80</td><td> 3.14</td><td> 5.94(0.75, 11.13)</td><td> 0.0252</td>
<td>Role / school</td><td> -1.41</td><td> -1.94</td><td> -0.53 (-5.43, 4.38)</td><td> 0.8324</td>
<td>Social</td><td> -1.68</td><td> 0.69</td><td> 2.37 (-2.66, 7.40)</td><td> 0.3530</td>
<td>Loading of</td><td> -0.99</td><td> -0.93</td><td> 0.06 (-5.84, 5.95)</td><td> 0.9851</td>
<td>treatment</td><td></td><td></td><td></td><td></td>
<td>Vitality</td><td> -1.88</td><td> 1.23</td><td> 3.11 (-2.91,9.13)</td><td> 0.3085</td>
<td>Weight</td><td> 4.72</td><td> 10.06</td><td> 5.34(-4.38, 15.06)</td><td> 0.2792</td>
For the EE population, the mean changes from baseline to Day 28 for respiratory factors measured by the CFQ-R for treatment groups of patients who received placebo, 120 mg daily, 240 mg daily and 240 mg twice a day were 1.6, 1.0, 5.2 and
3.0 units, respectively. For the MITT population, • if fr / tí íi (/ - '·. <·>,
MEXICAN INSTITUTE '·. -, .- £ 5 of ΙΛ,. »<>;
INWÍTKJAL *** _ ¿T; -mean changes from baseline to Day 28 for respiratory factors for treatment groups of patients administered placebo,
120 mg daily, 240 mg daily and 240 mg twice daily were 2.0, 0.3, 3.0 and
1.7 units, respectively. The 240 mg twice daily group in the EE population demonstrated a statistically significant improvement in respiratory score on Day 14.
The CFQ-R appetite score also showed improvement with the difference in the 240 mg twice daily group in the MITT population showing statistically significant improvement on Day 28.
Time for the patient's need for antimicrobial anti-pseudomonas
The time for administration of intravenous / oral / inhaled anti-pseudomonas antimicrobials was measured from Day 1 to the final visit for patients with at least one of the following: decreased exercise tolerance, increased cough, increased sputum / chest congestion and decreased appetite. The proportion of patients who required anti-pseudomonas antimicrobials (inhaled or systemic) over time was analyzed using a Cox proportional risk model. Table 25 summarizes the results for the time to need anti-pseudomonas antimicrobials for EE populations and
100
IMPI
<img file="MX353288B_D0119.tif" />
MITT.
TABLE 25
<td colspan="2" rowspan="2"></td><td colspan="5">EE and MITT populations - time parameters for the need for antimlcrobial anti-pseudomonas</td>
<td>Placebo (N = 32)</td><td>120 mg levofloxacin QD (N = 35)</td><td>240 mg levofloxacin QD (N = 35)</td><td>240 mg levofloxacin IDB (N = 34)</td><td>240 mg levofloxacin combined QD and IDB (N = 69)</td>
<td rowspan="3">EE population</td><td>Patients who required antimicrobial antipseudomonas</td><td> 40.6%</td><td> 20.0%</td><td> 25.7%</td><td> 20.6%</td><td> 23.2%</td>
<td>Risk ratio [95% Cl]</td><td></td><td> 0.39 [0.15, 1.01]</td><td> 0.48 [0.20, 1.17]</td><td> 0.26 [0.10, 0.69]</td><td> 0.37 [0.17, 0.81]</td>
<td>P value</td><td></td><td> 0.0522</td><td> 0.1050</td><td> 0.0067</td><td> 0.0123</td>
<td rowspan="3">Population MITT</td><td>Number (%) of patients requiring antimicrobial antipseudomonas</td><td> 48.6%</td><td> 18.4%</td><td> 27.0%</td><td> 20.5%</td><td> 23.7%</td>
<td>Risk ratio [95% Cl]</td><td></td><td> 0.29 [0.12, 0.71]</td><td> 0.39(0.17, 0.87]</td><td> 0.21 [0.09, 0.52]</td><td> 0.30 [0.15, 0.60]</td>
<td>P value</td><td></td><td> 0.0069</td><td> 0.0215</td><td> 0.0007</td><td> 0.0007</td>
The measured need for additional anti-pseudomonal microbes was reduced in all levofloxacin treatment groups. In addition, significant proportions of risk were observed in all levofloxacin treatment groups. Risk ratios are related to the relative risk that an event may occur. Risk ratios were 0.29 for the 120 mg group
<td></td><td> - 101 -</td><td></td><td>; í</td><td></td><td></td>
<td></td><td></td><td></td><td>Ϊ ', Γ.Ό</td><td></td><td>· '' «F ·. '*»</td>
<td>levofloxacin</td><td>daily, 0.39 for</td><td>the</td><td>group of 240</td><td>mg</td><td>of</td>
<td>levofloxacin al</td><td>day and 0.21 for</td><td>the</td><td>group of 240</td><td>mg</td><td>'•' «-. TTax -.— r. - of</td>
<td>levofloxacin two</td><td>times a day in</td><td>the</td><td colspan="2">MITT population</td><td>in</td>
<td>comparison with</td><td>The group of</td><td colspan="2">placebo, and</td><td colspan="2">were</td>
statistically significant compared to placebo. Figures 5 and 6 are representations of the survival distribution function over time for each treatment group and show that the survival distribution function for placebo-treated patients begins to drop in a shorter period than in patients. treated with levofloxacin. In sum, at least 240 mg twice daily showed significant efficacy over placebo on Day 28 in time for needing anti-pseudomonas antimicrobials.
Lung function evaluations
Changes in FEVi (forced expiration volume in 1 second), FVC (forced vital capacity) and FEF 25-75 (forced expiration flow 25-75%) were determined for patients from Day 1 to all visits. subsequent Tables 26 and 27 summarize the results for FEVi measurements in the EE and MITT populations, respectively. Figures 7 and 8 show graphs of the percentage change in FEVi (L) and the percentage change in FEVi (L) vs. Placebo, respectively, on Day 28 for the placebo-treated EE population, 120 mg daily, 240 mg daily
102
<img file="MX353288B_D0120.tif" />
IN.'TIT'JTO Mexican DE U KOHEÜAb INDUSTRIAL
<img file="MX353288B_D0121.tif" />
day or 240 mg twice a day.
graph of categorical change
Figure 9 shows one in the predicted FEVi on Day 2 8 for the EE population treated with 12 0 mg a day, 240 mg a day or 240 mg twice a day. Tables 28 and 29 summarize the results for the predicted FEVi measurements in the EE and MITT populations, respectively. Tables 30 and 31 summarize the results for FEF 25-75 measurements in the EE and
MITT, respectively.
TABLE 26
<td colspan="2" rowspan="2"></td><td colspan="5">EE population - changes in FEVi values</td>
<td>Placebo (N = 32)</td><td>120 mg levofloxaclna QD (N = 35)</td><td>240 mg levofloxacin QD (N = 35)</td><td>240 mg levofloxacin IDB (N = 34)</td><td>240 mg d levofl xacina combined QD and BID (N = 69)</td>
<td rowspan="2">Day 1</td><td>Average (SD)</td><td> 1.98 (0.61)</td><td> 1.99 (0.83)</td><td> 2.09 (0.75</td><td> 1.86 (0.68)</td><td> 1.98 (0.72)</td>
<td>Half</td><td> 2.01</td><td> 1.87</td><td> 2.02</td><td> 1.70</td><td> 1.81</td>
<td rowspan="2">Day 14</td><td>Average (SD)</td><td> 1.97 (0.63)</td><td> 2.00 (0.83</td><td> 2.16 (0.78)</td><td> 2.02 (0.76)</td><td> 2.09 (0.77)</td>
<td>Half</td><td> 1.93</td><td> 1.82</td><td> 2.09</td><td> 1.88</td><td> 2.03</td>
<td rowspan="3">Percent change from baseline to Day 14</td><td>Average (SD)</td><td> -0.89 (6.86)</td><td> 1.13(7.48)</td><td> 3.84(10.23)</td><td> 8.87(12.42)</td><td> 6.32(11.56)</td>
<td>Half</td><td> -0.17</td><td> 0.56</td><td> 1.92</td><td> 7.51</td><td> 3.94</td>
<td>P value vs. placebo</td><td></td><td> 0.4940</td><td> 0.0737</td><td> 0.0001</td><td> 0.0013</td>
<td rowspan="2">Day 28</td><td>Average (SD)</td><td> 1.95 (0.65)</td><td> 2.03 (0.89)</td><td> 2.13(0.76)</td><td> 1.90 (0.68)</td><td> 2.02 (0.73)</td>
<td>Half</td><td> 1.91</td><td> 1.91</td><td> 2.15</td><td> 1.79</td><td> 1.98</td>
<td rowspan="3">Percent change from baseline to Day 28</td><td>Average (SD)</td><td> -2.55 (10.37)</td><td> 1.71 (9.73)</td><td> 2.51 (13.25)</td><td> 5.05(11.49)</td><td> 3.75(12.40)</td>
<td>Half</td><td> -3.91</td><td> 1.60</td><td> 1.28</td><td> 4.55</td><td> 2.80</td>
<td>P value vs. placebo</td><td></td><td> 0.1726</td><td> 0.1121</td><td> 0.0102</td><td> 0.0168</td>
- 103 IMPI
TABLE 27
<img file="MX353288B_D0122.tif" />
MEXICAN INSTITUTE
EU THE HtOHWAD
INDUSTRIAL
<img file="MX353288B_D0123.tif" />
<td colspan="2" rowspan="2"></td><td colspan="5">MITT population - changes in FEVi values</td>
<td>Placebo (N = 37)</td><td>120 mg levofloxacin QD (N = 38)</td><td>240 mg levofloxacin QD (N = 37)</td><td>240 mg levofloxacin IDB (N = 39)</td><td>240 mg levofloxacin combined QD and IDB (N = 76)</td>
<td rowspan="2">Day 1</td><td>Average (SD)</td><td> 1.94 (0.61)</td><td> 1.95 (0.81)</td><td> 2.05 (0.75)</td><td> 1.88 (0.68)</td><td> 1.96 (0.71)</td>
<td>Half</td><td> 1.97</td><td> 1.83</td><td> 1.90</td><td> 1.70</td><td> 1.80</td>
<td rowspan="2">Day 14</td><td>Average (SD)</td><td> 1.92 (0.63)</td><td> 1.97 (0.81)</td><td> 2.12 (0.78)</td><td> 2.04 (0.77)</td><td> 2.08 (0.77)</td>
<td>Half</td><td> 1.92</td><td> 1.79</td><td> 2.04</td><td> 1.90</td><td> 1.97</td>
<td rowspan="3">Percent change from baseline to Day 14</td><td>Average (SD)</td><td> -1.21 (6.46)</td><td> 1.87 (9.41)</td><td> 3.81 (10.32)</td><td> 9.34(13.72)</td><td> 6.61 (12.40)</td>
<td>Half</td><td> -0.90</td><td> 0.56</td><td> 1.92</td><td> 7.51</td><td> 3.94</td>
<td>P value vs. placebo</td><td></td><td> 0.2873</td><td> 0.0497</td><td> <0001</td><td> 0.0005</td>
<td rowspan="2">Day 28</td><td>Average (SD)</td><td> 1.89 (0.64)</td><td> 1.99 (0.88)</td><td> 2.09 (0.76)</td><td> 1.93 (0.69)</td><td> 2.01 (0.73)</td>
<td>Half</td><td> 1.85</td><td> 1.83</td><td> 2.10</td><td> 1.82</td><td> 1.95</td>
<td rowspan="3">Percent change from baseline to Day 28</td><td>Average (SD)</td><td> -2.96 (9.81)</td><td> 1.92 (9.95)</td><td> 2.35(13.03)</td><td> 5.93(15.07)</td><td> 4.14(14.11)</td>
<td>Half</td><td> -3.92</td><td> 1.60</td><td> 1.28</td><td> 3.55</td><td> 2.50</td>
<td>P value vs. placebo</td><td></td><td> 0.1292</td><td> 0.0831</td><td> 0.0026</td><td> 0.0063</td>
104
<img file="MX353288B_D0124.tif" />
<img file="MX353288B_D0125.tif" />
TABLE 28
<td colspan="2" rowspan="2"></td><td colspan="5">EE population - changes in% predicted FEVi</td>
<td>Placebo (N = 32)</td><td>120 mg levofloxacin QD (N = 35)</td><td>240 mg levofloxacin QD (N = 35)</td><td>240 mg levofloxacin IDB (N = 34)</td><td>240 mg levofloxacin combined QD and IDB (N = 69)</td>
<td rowspan="2">Day 1</td><td>Average (SD)</td><td> 54.4 (12.93)</td><td> 54.0(17.79)</td><td> 55.9(14.60)</td><td> 48.2(14.88)</td><td> 52.1 (15.13)</td>
<td>Half</td><td> 54.5</td><td> 53.0</td><td> 56.0</td><td> 45.5</td><td> 51.0</td>
<td rowspan="2">Day 14</td><td>Average (SD)</td><td> 53.9 (13.21)</td><td> 54.7(17.61)</td><td> 57.7(15.19)</td><td> 51.7(16.93)</td><td> 54.7(16.23)</td>
<td>Half</td><td> 54.5</td><td> 53.0</td><td> 62.0</td><td> 49.5</td><td> 52.0</td>
<td rowspan="2">Relative percentage change from baseline to Day 14</td><td>Average (SD)</td><td> -0.77 (6.85)</td><td> 1.77 (6.08)</td><td> 3.57(10.75)</td><td> 7.67(14.70)</td><td> 5.59 (12.92)</td>
<td>Half</td><td> 0.00</td><td> 1.15</td><td> 1.52</td><td> 7.42</td><td> 4.00</td>
<td rowspan="2">Day 28</td><td>Average (SD)</td><td> 53.1 (14.05)</td><td> 55.0(19.30)</td><td> 57.3(15.52)</td><td> 50.5 (15.36)</td><td> 54.0(15.71)</td>
<td>Half</td><td> 55.0</td><td> 52.0</td><td> 58.0</td><td> 49.0</td><td> 54.0</td>
<td rowspan="3">Relative percentage change from baseline to Day 28</td><td>Average (SD)</td><td> -2.47 (10.34)</td><td> 1.82 (9.81)</td><td> 2.99(14.54)</td><td> 7.39(17.48)</td><td> 5.13(16.06)</td>
<td>Half</td><td> -3.74</td><td> 2.30</td><td> 0.00</td><td> 4.88</td><td> 4.00</td>
<td>P value</td><td></td><td> 0.2655</td><td> 0.1411</td><td> 0.0034</td><td> 0.0113</td>
105
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<img file="MX353288B_D0126.tif" />
TABLE 29
<td colspan="2" rowspan="2"></td><td colspan="5">MITT population - changes in% predicted FEVi</td>
<td>Placebo (N = 37)</td><td>120 mg levofloxacin QD (N = 38)</td><td>240 mg levofloxacin QD (N = 37)</td><td>240 mg levofloxacin IDB (N = 39)</td><td>240 mg of levofloxacin combined QD and IDB (N = 76)</td>
<td rowspan="2">Day 1</td><td>Average (SD)</td><td> 52.4 (13.42)</td><td> 52.9(17.68)</td><td> 55.4(14.41)</td><td> 48.8(15.15)</td><td> 52.0(15.07)</td>
<td>Half</td><td> 53.0</td><td> 53.0</td><td> 56.0</td><td> 46.0</td><td> 51.0</td>
<td rowspan="4">Day 14</td><td>Average (SD)</td><td> 51.7 (13.84)</td><td> 53.9(17.42)</td><td> 57.1 (14.96)</td><td> 52.1 (17.16)</td><td> 54.6(16.20)</td>
<td>Half</td><td> 53.0</td><td> 53.0</td><td> 61.0</td><td> 49.5</td><td> 52.0</td>
<td>Average (SD)</td><td> -0.68 (3.37)</td><td> 0.81 (3.24)</td><td> 1.70 (5.39)</td><td> 3.66 (7.49)</td><td> 2.69 (6.57)</td>
<td>Half</td><td> -1.00</td><td> 1.00</td><td> 1.00</td><td> 2.50</td><td> 2.00</td>
<td rowspan="3">Relative percentage change from baseline to Day 14</td><td>Average (SD)</td><td> -1.30 (6.58)</td><td> 2.46 (8.47)</td><td> 3.51 (10.83)</td><td> 8.30(15.80)</td><td> 5.93(13.70)</td>
<td>Half</td><td> -1.89</td><td> 1.15</td><td> 1.52</td><td> 7.42</td><td> 4.00</td>
<td>P value</td><td></td><td> 0.2284</td><td> 0.0780</td><td> 0.0005</td><td> 0.0025</td>
<td rowspan="2">Day 28</td><td>Average (SD)</td><td> 50.9 (14.46)</td><td> 54.1 (19.19)</td><td> 56.7(15.33)</td><td> 50.8(15.40)</td><td> 53.8(15.54)</td>
<td>Half</td><td> 52.0</td><td> 50.0</td><td> 54.0</td><td> 49.0</td><td> 53.5</td>
<td rowspan="3">Relative percentage change from baseline to Day 28</td><td>Average (SD)</td><td> -3.08 (9.82)</td><td> 2.00(10.07)</td><td> 2.77(14.30)</td><td> 7.97(19.49)</td><td> 5.37(17.18)</td>
<td>Half</td><td> -3.77</td><td> 2.30</td><td> 0.00</td><td> 4.44</td><td> 3.85</td>
<td>P value</td><td></td><td> 0.1759</td><td> 0.0888</td><td> 0.0008</td><td> 0.0036</td>
106
TABLE 30
<img file="MX353288B_D0127.tif" />
iN'STiTim, · Mexican De La PM / PIÍIíAD INIJUSTUAL '' '•• «• RS *.
<td colspan="2" rowspan="2"></td><td colspan="5">EE population - changes in FEF values 25-75</td>
<td>Placebo (N = 32)</td><td>120 mg levofloxaclna QD (N = 35)</td><td>240 mg levofloxaclna QD (N = 35)</td><td>240 mg levofloxaclna IDB (N = 34)</td><td>240 mg levofloxacline combined QD and IDB (N = 69)</td>
<td rowspan="2">Day 1</td><td>Average (SD)</td><td> 1.02 (0-57)</td><td> 1.17(0.78)</td><td> 1.22 (0.84)</td><td> 0.85 (0.53)</td><td> 1.04 (0.72)</td>
<td>Half</td><td> 0.94</td><td> 0.98</td><td> 1.10</td><td> 0.68</td><td> 0.83</td>
<td rowspan="2">Day 14</td><td>Average (SD)</td><td> 1.03 (0.64)</td><td> 1.18(0.83)</td><td> 1.33 (0.93)</td><td> 1.00 (0.78)</td><td> 1.17(0.87)</td>
<td>Half</td><td> 0.86</td><td> 0.99</td><td> 1.11</td><td> 0.78</td><td> 0.92</td>
<td rowspan="3">Percent change from baseline to Day 14</td><td>Average (SD)</td><td> 1.95 (19.45)</td><td> 0.41 (12.28)</td><td> 9.58 (21.16)</td><td> 16.99 (32.60)</td><td> 13.23 (27.45)</td>
<td>Half</td><td> -1.72</td><td> 0.45</td><td> 4.41</td><td> 11.66</td><td> 8.79</td>
<td>P value</td><td></td><td> 0.6634</td><td> 0.2532</td><td> 0.0072</td><td> 0.0275</td>
<td rowspan="2">Day 28</td><td>Average (SD)</td><td> 1.00 (0.64)</td><td> 1.23 (0.93)</td><td> 1.27 (0.88)</td><td> 0.93 (0.59)</td><td> 1.10(0.77)</td>
<td>Half</td><td> 0.94</td><td> 1.03</td><td> 1.15</td><td> 0.78</td><td> 0.97</td>
<td rowspan="3">Percent change from baseline to Day 28</td><td>Average (SD)</td><td> -2.73 (16.74)</td><td> 0.73(15.76)</td><td> 4.70(16.11)</td><td> 13.11 (28.50)</td><td> 8.78 (23.19)</td>
<td>Half</td><td> -4.61</td><td> 2.70</td><td> 5.77</td><td> 5.71</td><td> 5.74</td>
<td>P value</td><td></td><td> 0.6038</td><td> 0.2223</td><td> 0.0007</td><td> 0.0076</td>
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INDUSTRIAL PROPERTY
<img file="MX353288B_D0128.tif" />
TABLE 31
<td colspan="2" rowspan="2"></td><td colspan="5">MITT population - changes in FEF values 25-75</td>
<td>Placebo (N = 37)</td><td>120 mg levofloxacin QD (N = 38)</td><td>240 mg levofloxacin QD (N = 37)</td><td>240 mg levofloxacin IDB (N = 39)</td><td>240 mg levofloxacin combined QD and IDB (N = 76)</td>
<td rowspan="2">Day 1</td><td>Average (SD)</td><td> 0.98 (0.55)</td><td> 1.12 (0.77)</td><td> 1.18(0.83)</td><td> 0.87 (0.53)</td><td> 1.02 (0.71)</td>
<td>Half</td><td> 0.92</td><td> 0.89</td><td> 1.09</td><td> 0.68</td><td> 0.83</td>
<td rowspan="2">Day 14</td><td>Average (SD)</td><td> 0.97 (0.63)</td><td> 1.15(0.82)</td><td> 1.29 (0.92)</td><td> 1.01 (0.78)</td><td> 1.15(0.86)</td>
<td>Half</td><td> 0.81</td><td> 0.85</td><td> 1.08</td><td> 0.78</td><td> 0.90</td>
<td rowspan="3">Percent change from baseline to Day 14</td><td>Average (SD)</td><td> -1.78 (22.86)</td><td> 1.73 (13.76)</td><td> 9.53 (20.70)</td><td> 16.70 (31.72)</td><td> 13.16(26.92)</td>
<td>Half</td><td> -4.46</td><td> 1.35</td><td> 4.41</td><td> 11.66</td><td> 8.79</td>
<td>P value</td><td></td><td> 0.5910</td><td> 0.0699</td><td> 0.0007</td><td> 0.0027</td>
<td rowspan="2">Day 28</td><td>Average (SD)</td><td> 0.94 (0.62)</td><td> 1.20 (0.92)</td><td> 1.23 (0.87)</td><td> 0.95 (0.61)</td><td> 1.09 (0.76)</td>
<td>Half</td><td> 0.91</td><td> 0.83</td><td> 1.12</td><td> 0.82</td><td> 0.93</td>
<td rowspan="3">Percent change from baseline to Day 28</td><td>Average (SD)</td><td> -6.40 (20.27)</td><td> 1.94 (16.55)</td><td> 5.02 (15.98)</td><td> 14.19(28.56)</td><td> 9.61 (23.44)</td>
<td>Half</td><td> -8.66</td><td> 3.38</td><td> 5.77</td><td> 7.46</td><td> 5.88</td>
<td>P value</td><td></td><td> 0.1241</td><td> 0.0489</td><td> <0001</td><td> 0.0003</td>
In the EE population, LVEF values for patients administered 240 mg of levofloxacin twice daily increased from a mean value of 1.70 L on Day 1 (baseline) to 1.79 L on Day 28. , representing an increase in FEVi from approximately 5%. In patients receiving 240 mg of levofloxacin daily, FEVi values increased from a mean value of 2.02 L on Day 1 to a mean value of
108
<img file="MX353288B_D0129.tif" />
2.15 L on Day 28, representing an incr from approximately 6%. In patients receiving 120 mg of levofloxacin daily, FEVi values increased from a mean value of 1.87 L on Day 1 to a mean value of 1.91 L on Day 28, representing an increase in FEVi from approximately 2 %. The greatest differences for FEVi between patients who received placebo and patients who received levofloxacin were 0.16 L on Day 14 and 0.24 L on Day 28.
In the MITT population, FEVi values for patients administered 240 mg of levofloxacin twice daily increased from a mean value of 1.70 L on Day 1 (baseline) to 1.82 L on Day 28. , representing an increase in FEVi from approximately 7%. In patients who received 240 mg of levofloxacin daily, FEVi values increased from a mean value of 1.90 L on Day 1 to a mean value of 2.10 L on Day 28, representing an increase in FEVi from approximately 10 %. The greatest differences for FEVi between patients who received placebo and patients who received levofloxacin were 0.12 L on Day 14 and 0.25 L on Day 28.
The FEF 25-75 values refer to the average flow
- 109 IMPI
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INDUSTRIAL
<img file="MX353288B_D0130.tif" />
of air exiting the lungs during the average JJOT'üiÓli of expiration. In minor respiratory diseases this value can be reduced. In the EE population, FEF 25-75 values for patients administered 240 mg of levofloxacin twice daily increased from a mean value of 0.68 on Day 1 (baseline) to 0.78 on Day 28. , representing an increase in FEF 25-75 from approximately 15%. In patients receiving 240 mg levof loxacin daily, FEF 25-75 values increased from a mean value of 1.10 on Day 1 to a mean value of 1.15 on Day 28, representing an increase in FEF 25-75 from about 4%. In patients receiving 120 mg levofloxacin daily, FEF 25-75 values increased from a mean value of 0.98 on Day 1 to a mean value of 1.03 on Day 28, representing an increase in FEF 25-75 from about 5%. The greatest differences for the FEF 25-75 between patients who received placebo and patients who received levofloxacin were 0.25 L on Day 14 and 0.21 L on Day 28.
In the MITT population, the FEF 25-75 values for patients administered 240 mg of levofloxacin twice daily increased from a mean value of 0.68 on Day 1 (baseline) to 0.82 on
110 jl Jfe- - - -í V-xD '·
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FEF 25-75 from an increase in patients to whom, daily, FEF 25-75 values were administered on Day 28, representing approximately 20%. In 240 mg of levofloxacin they increased from a mean value of 1.09 on Day 1 to a mean value of 1.12 on Day 28, representing an increase in FEF 25-75 from approximately 3. The largest differences for FEF 25-75 between patients receiving placebo and patients receiving levofloxacin were 0.27 L on Day 14 and 0.21 L on Day 28.
Security Assessments
Adverse events and intolerance to the drug were evaluated from Day 1 to the end of the study. No significant adverse events were reported.
Fluoroquinolone-induced arthralgia and myalgia have previously been reported in the use of some fluoroquinolones, for example, in the treatment of sinusitis (Lee-Lee T., et al., Fluoroquinilone-induced arthralgia and myalgia in the treatment of sinusitis (Artralgia and Fluoroquinolone-Induced Myalgia in the Treatment of Sinusitis) Am J Rhinol (2005) 19: 395-9, incorporated by reference in its entirety). In this study, arthralgia was reported in 5.4% of patients given placebo. Arthralgia was not reported in patients who received any formulation of levofloxacin.
IMPI
MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY
Example 3 - Phase 1 Clinical Study in Patients
<img file="MX353288B_D0131.tif" />
CF pediatric
An open multi-center study was conducted in
Phase 1 to assess the safety, tolerability and pharmacokinetics of weight-adjusted doses of levofloxacin formulated with MgC12 administered once daily for 14 days to pediatric stable CF patients. Patients were divided into 2 groups based on their age: 6 to 11 years of age and 12 to 16 years of age. The daily administered dose of levofloxacin formulated with MgC12 was divided as follows: patients who weighed from 14 to 21 kg received a dose of 120 mg, patients who weighed from 22 to 3 0 kg received a dose of 180 mg, and patients who weighed more than 30 kg received a dose of 240 mg. A total of 27 patients were enrolled and all patients completed the study. There were 14 patients in the 6 to 11 year old group and 13 patients in the 12 to 16 year old group. Seven patients (all in the 6-11 age group) received 180 mg daily of levofloxacin formulated with MgCl<sub>2</sub>. Figure 10 shows a dose-normalized serum AUC graph in pediatric CF patients. the patient's body weight. Figures 11A and 9B show graphs of dose-normalized serum AUC in pediatric CF patients. the age of the patient and vs. BSA, respectively. Figures 11C and 9E show graphs
112 you-you.
Of the C<sub>max</sub> in serum normalized by the dose in patients r? .1 ·. · / Í · ί * .tí. . · ..
ÍNSTIT-J i ''. · H'a'C. ' O € la ♦ c ?; > CF pediatric INi / U'Tii vs. the patient's body weight, vs.
the age of the patient and vs. BSA, respectively.
Exposures to levofloxacin in serum with either the 180 or 240 mg dose of levofloxacin formulated with
MgCl<sub>2</sub> they appeared to be in the ranges observed in adult CF patients studied in a related clinical trial (data not shown).
Example 4 - Phase III Clinical Study
A double-blind, randomized, multinational, multi-center, placebo-controlled study was conducted in
Phase 3 to evaluate the efficacy and safety of levofloxacin formulated with MgCl<sub>2</sub> in patients with
Stable CF. After a 14-day examination period, patients were randomly selected at Visit 1 / Day 1 at a ratio of
2: 1 to receive levofloxacin formulated with MgCl<sub>2</sub> or placebo.
Random selection is stratified by geographic region (from
EU
vs.
non-EU), by age (12 to 18 years old) and by predicted FEVi percentage (<
55% vs.
55%) .
Patients received 28 days of either levofloxacin formulated with MgCl<sub>2</sub> or placebo followed by days of observation. Patients should remain without the antimicrobial anti-pseudomonas drug, different study (levofloxacin formulated with MgCl<sub>2</sub> or placebo) and maintenance oral azithromycin (if
113 applicable), during the course of the study to less than
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<img file="MX353288B_D0132.tif" />
met the defined definition protocol of an exacerbation or less than was determined necessary for safety reasons by the researchers. The end of the study is defined as the last visit of the last patient.
Levofloxacin formulated with MgCl<sub>2</sub> (levofloxacin inhalation solution, Aeroquin ™) will be provided in single-dose vials ready for administration. Each ampule contains 240 mg of levofloxacin formulated with MgCl<sub>2 </sub>in 2.4 ml (100 mg / ml). A dose of 240 mg (1 ampule) was administered using a PARI eFlow® Research Twice Daily Nebulizer (BID) with a separation of approximately 8 to 12 hours. The placebo is riboflavin 5'phosphate (solubilized from vitamin B2) in 0.9% saline provided in single-use ampules ready for administration. Each vial contains 9.6 pg of 5'-phosphate riboflavin in a volume of 2.4 ml. The PARI eFlow® Research Nebulizer was optimized and designed for use only with levofloxacin formulated with MGC1<sub>2</sub>. Both levofloxacin formulated with MgCl<sub>2</sub> as the placebo control they were administered using this nebulizer system. Analysis populations included: (1) safety / modified attempt to treat (MITT) population (all patients enrolled in the study who received at least one dose of study drug (levofloxacin formulated with
- 114 MgC12 or placebo); (2) population of evaluable efficacy (all
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<img file="MX353288B_D0133.tif" />
patients enrolled in the study, without major protocol violations, who received at least 80% of the study drug doses (levofloxacin formulated with MgC12 / placebo); and (3) pharmacokinetic population (all patients who received at least one dose of the study drug (levofloxacin formulated with MgC12 / placebo) and from whom at least one pharmacokinetic (PK) sample of blood or sputum was collected).
The inclusion criteria for the study patients included: at least 12 years of age; weight of at least 3 0 kg or 66 pounds; and have a documented diagnosis of CF evidenced by one or more of the clinical characteristics consistent with the CF phenotype. Exclusion criteria for study patients included: the use of a research agent within 28 days prior to the visit 1; the use of some nebulized or systemic active antimicrobial against P. aeruginosa within 28 days prior to Visit 1, different from maintenance oral azithromycin, which must have been started at least 28 days before Visit 1; and the use of oral corticosteroids in doses that exceed the equivalent of 10 mg of prednisone / day or 2 0 mg of prednisone every third day in the examination or in the Visit. Primary efficacy evaluations
The primary endpoint includes the
115
<img file="MX353288B_D0134.tif" />
ΙΝΤΠΤυΤΟ MEXICANO OF. M FXCFICOAP INDUSTRIAL time (in days) for an exacerbation from baseline (Visit 1 / Day 1) to the final visit. To meet the endpoint a patient must concurrently meet 4 of the 12 symptoms / signs that make up the Fuchs definition of an exacerbation (Fuchs HJ, et al., Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis (Effect of recombinant human DNase aerosol on exacerbations of respiratory symptoms and lung function in patients with cystic fibrosis) N. Engl J Med 1994; 331: 637-642, incorporated by reference in its entirety).
The 12 symptoms / signs defined by the Fuchs criterion include: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; discomfort; fatigue or lethargy; temperature above 38 ° C; anorexia or weight loss; pain or tenderness of the sinuses; change in discharge from the sinuses; change in physical examination of the chest; decrease in lung function by 1% or more from a previously recorded value; and radiographic changes indicative of lung infection.
Previous symptoms associated with an exacerbation of each patient are recorded using a standard questionnaire, the respiratory symptoms questionnaire, and
<img file="MX353288B_D0135.tif" />
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<img file="MX353288B_D0136.tif" />
systemic (RSSQ) at patient visits. Changes in the patient's experiences are relative to what the patient considers normal on a daily basis. Patients administered with MgCl formulated aerosolized levofloxacin are anticipated.<sub>2</sub> They provide the following signs / symptoms that are included in the Fuchs criterion and that are recorded using the RSSQ:
(1) Increased sputum production: patients have no change, slightly less or much less sputum when coughing.
(2) Change in the appearance of sputum: for sputum thickness, patients have thin or very thick sputum; for sputum color, patients have better sputum color (better increases from brown -> green -> yellow -> transparent).
(3) Increased chest congestion: Patients have little or no decrease in chest congestion.
(4) New or increased coughing up blood: Patients have little or no decrease in the amount of coughing up blood.
less frequently or much less frequently.
(5) Increased cough: for the intensity of the cough, patients have light or very light coughs;
for the frequency of cough, patients cough a little
117 (6) Decreased exercise tolerance: the íItTiWO L · i. ·.
Patients carry out their daily activities, eg, climbing stairs, a little more easily or much more easily.
with exercise: patients breathe a little easier or much easier when they carry out their daily activities.
(8) Discomfort, fatigue or lethargy: patients have a little more energy or a lot more energy since the last visit.
(9) Fever: patients have not had a fever since the last visit.
(10) Weight loss: patients have no weight change, or a slight increase.
(11) Sinus pain and tenderness: Patients have no pain or tenderness.
(12) Change in discharge from the sinuses: the patient has a better discharge from the sinuses (a decrease in thickness and / or a better color).
(13) Absenteeism from school or work (due to illness): patients are not absent from their scheduled activities.
(14) Decreased appetite: Patients have a small increase in appetite.
Secondary Efficacy Assessments
Secondary endpoints include
118 clinical features
IMPI
INSTITUTO MEXICANO ok u INDUSTRIAL reorietuv of pulmonary function, microbiolc
<img file="MX353288B_D0137.tif" />
and results reported by the patient.
<img file="MX353288B_D0138.tif" />
Clinical features
The clinical characteristics include the time (in days) for the administration of systemic antimicrobial antipseudomonas (oral or IV) and / or inhaled from the baseline (Visit 1 / Day 1) until the final visit. To meet this endpoint, patients must have at least one of four worsened respiratory symptoms (increased cough, increased sputum / chest congestion, decreased exercise tolerance, decreased appetite) at the time of antimicrobial agent administration -pseudomonas. Clinical features also include the proportion of patients who missed at least one day of school / work secondary to worsening respiratory status.
It is anticipated that patients who were administered aerosolized levofloxacin formulated with MgCl<sub>2 </sub>they have an increased time of administration of systemic anti-pseudomonas antimicrobials (oral or IV) and / or inhaled from the baseline (Visit 1 / Day 1) until the final visit compared to the patients who were administered placebo. In addition, the proportion of patients who were administered aerosolized levofloxacin formulated with MgCl<sub>2</sub> who missed at least 1 day of school / work
119
<img file="MX353288B_D0139.tif" />
less
F; Β Λ Τ
L · 1.ί j. _ & iNST; 'rt; A> Mz<sub>TO</sub>/ c_<sub>i?</sub>L *
OI LA PlC'r! VU * ¿tKPUS IMAI secondary to worsening respiratory status is the proportion of patients given placebo who missed at least 1 day of school / work secondary to worsening respiratory status.
Characteristics of lung function
Lung function characteristics include: percentage change in FEV1 (L) from baseline to Day 28; relative change in FEV1 (predicted percentage) from baseline to Day 28; percentage change in FEF 25-75 (L / s) from baseline to Day 28; percentage change in FVC (L) from baseline to Day 28; and categorical evaluation of the percentage change in FEV1 (L) and the relative change in FEV1 percentage predicted from baseline to Day 28.
It is anticipated that patients who were administered aerosolized levofloxacin formulated with MgCl<sub>2 </sub>they have more advantageous characteristics of lung function compared to patients who received placebo.
Microbiology characteristics
Microbiological characteristics include: change in density of P. aeruginosa (logio colony forming units [CFU] per gram of sputum) from baseline to Day 28; categorical evaluation of the change in the density of P. aeruginosa (logio forming units of
120
IMPI
MEXICAN INDUSTRIAL INSTITUTE
<img file="MX353288B_D0140.tif" />
colony [CFU] per gram of sputum) from baseline to
Day 28; and change in the density of Stenotrophomonas sp.,
<td colspan="2">Achromobac t er</td><td>sp.,</td><td colspan="2">Burkholderia</td><td>sp. ,</td><td>and</td><td>S. aureus</td><td>(logio</td>
<td>units</td><td colspan="2">forming</td><td>of</td><td>Suburb</td><td>[CFU]</td><td>by</td><td>gram of</td><td>sputum)</td>
<td>from the</td><td>line</td><td>basal</td><td>to the</td><td>Day 28.</td><td></td><td></td><td></td><td></td>
<td></td><td>I know</td><td colspan="2">anticipates</td><td>that the</td><td colspan="2">patients</td><td>to the</td><td>That</td>
administered aerosolized levofloxacin formulated with MgC12 have more advantageous microbiological characteristics, eg, decreased density of P. aeruginosa in sputum, decreased density of Stenotrophomonas sp., Achromobacter sp., Burkholderia sp., and S. aureus in sputum, compared to patients who received placebo.
Characteristics of the result reported by the patient.
The characteristics of the result reported by the patient include: change in the respiratory domain of the CFQ-R from the baseline on day 28; and categorical evaluation of the change in the respiratory domain of the CFQ-R from baseline to Day 28.
Patients administered levofloxacin formulated with MgCl are anticipated<sub>2</sub> it has more advantageous characteristics of the result reported by the patient than the patients who received placebo. Example 5 - In vivo antibacterial activity of the levofloxaclna solution for inhalation against Burkholderia cepacia
Burkholderia cepacia is an opportunistic pathogen
121 capable of causing lung infection in CF patients.
IKSTIT 'TO MCXICArk? OF THE INDUSTRIAL FRVPIFDaO
<img file="MX353288B_D0141.tif" />
Infections with cepacia syndrome Certain strains of B. cepacia cause that characterized by progressive and invasive necrotizing pneumonia and septicemia. Most B. cepacia have high MICs for many antibiotics. Aerosolized levofloxacin formulated with MgC12 allows the aerosol delivery of high concentrations of the drug to the lung.
Five strains of B. cepacia were tested with levofloxacin MICs ranging from 0.25 to 8 mg / L in a mouse model of lung infection. Female BALB / c mice were injected with 150 mg / kg cyclophosphamide 3 days prior to infection. On day 4, mice were infected with 50 µΐ of bacterial suspension (~ 10<sup>6</sup> CFU / ml) using a curved syringe for oral drop-tip feeding under isoflurane anesthesia. Treatment with levofloxacin formulated with MgCl<sub>2</sub> (60 mg / kg twice daily) or with saline only, started 72 hours after infection and continued twice daily for four days using a micro-spray aerosol device. Sixteen hours after the last treatment, mice were sacrificed, lungs harvested, homogenized, and plated to determine colony counts (CFU).
As part of the Phase 2b test of the
122 aerosolized levofloxacin formulated with MgCl<sub>2</sub> in patients
IMPI MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY
<img file="MX353288B_D0142.tif" />
with CF, a 16-year-old male patient infected with B. cepacia (MIC of levofloxacin => 128 mg / L) received 240 mg of levofloxacin formulated with MgCl<sub>2</sub> daily for 28 days.
Aerosolized levofloxacin formulated with MgCl<sub>2</sub> produced at least one log CFU of bacterial kill for all strains in the mouse infection model (Table 32). In the CF patient, a decrease of 1.7 log CFU was observed in the bacterial counts for 28 days.
TABLE 32
<td></td><td colspan="3">Genomovar II</td><td colspan="2">Genomovar lll</td>
<td>Strains</td><td>BC1012</td><td>BC1013</td><td>BC1014</td><td>BC1020</td><td>BC1021</td>
<td>MIC (mg / L)</td><td> 4</td><td> 0.25</td><td> 1</td><td> 8</td><td> 8</td>
<td>Average change in</td><td> -1.03</td><td> -2.08</td><td> -1.47</td><td> -1.11</td><td> -1.35</td>
<td>Log CFU / lungs</td><td></td><td></td><td></td><td></td><td></td>
An increase in the FEV1 of the CF patient was observed. On day 1 of the study, the patient's FEV1 was 1.21 L, this increased to 1.3 0 L on day 28, an improvement of 7%. From a population model, Cmax and AUC values were calculated to be from approximately 12,900 mg / L and 4,400 mg * h / L, respectively.
Aerosol administration of levofloxacin formulated with MgCl<sub>2</sub> produced significant bacterial destruction in strains with a wide range of MICs.
The
123
IMPI non-clinical and clinical data support future clinical evaluation of levofloxacin formulated with MgC12 in the management of chronic lung infections due to B. cepacia.
Mexican INSTtTVTn
Of. THE fRVCEKMn IND> STÍUAl
<img file="MX353288B_D0143.tif" />
To the extent that the publications and patents or patent applications incorporated by reference herein contradict the description contained in the specification, the specification is intended to exceed and / or take precedence over any such contradictory material.
Unless defined otherwise, all terms (including technical and scientific terms) should be given their ordinary and customary meanings by the person skilled in the art and should not be limited to a special meaning or adapted to less than defined. expressly so herein.
The terms and phrases used in this application, and their variations, unless specifically defined otherwise should be interpreted openly as opposed to limiting. As examples of the foregoing, the term "including" should be understood to mean "including, without limitation" or the like; the term "comprising" as used herein is synonymous with "including", "containing" or "characterized by", and is inclusive or open and does not exclude additional elements or method steps not cited; the term 'example' is used to provide exemplary cases of the concept under discussion, not as a list
124
Exhaustive or limiting IMPI thereof; adjectives such as
ΙΝ'ΤΤΤ'ΓΓτ) mmicanu OE LA HKWUtUñ WvCTWaí
<img file="MX353288B_D0144.tif" />
'known', 'normal', 'standard' and terms of similar meaning should not be construed as limiting the concept described to a given period of time or to an available concept as to a given time, but rather to be understood as encompassing technologies known, normal or standard that may be available or known now or at any time in the future; and the use of terms such as 'preferably', 'preferred', 'desired' or 'desirable', and words of similar meaning should not be understood to imply that certain characteristics are critical, essential or even important to the structure or function of the invention, but rather, are merely intended to highlight alternative or additional features that may or may not be used in a particular embodiment of the invention. Similarly, a group of concepts related to the conjunction 'and' should not be understood to require that each and every one of these concepts be present in the grouping, but rather should be understood as 'and / or' unless defined expressly otherwise. Similarly, a group of concepts related to the conjunction Ό 'should not be understood as requiring mutual exclusivity between that group, but rather should be understood as' and / or' unless less expressly defined otherwise. Also, as used in this application, the items 'a' and 'one' must
125
<img file="MX353288B_D0145.tif" />
interpreted referring to one or more than one (ie, at least of the article. By way of one) of the grammatical objects example, 'an element' means an element or more than one element.
The presence in some cases of extensive words and phrases such as limiting to ', or others which means that it narrows in cases in' one or more ',' at least ',' but without similar phrases, should not be understood as intended or required the case more where such extensive sentences may be absent.
It should be understood that all numbers expressing ingredient amounts, reaction conditions, and so on used in the specification are in all cases modified by the term "about". Therefore, unless otherwise indicated, the numerical parameters established herein are approximations that may vary depending on the desired properties that are sought to be obtained. At least, and not in an attempt to limit the application of the doctrine of equivalents to the scope of any claim in any application claiming priority for the present application, each numerical parameter should be interpreted in light of the number of significant digits and procedures in ordinary rounds.
Furthermore, although the above has been described in some
126
IMPI detail by way of illustration and examples for purposes of clarity and understanding, it is apparent to those skilled in the art that certain changes and modifications may be practiced.
In consecuense,
WÍTmm MEXICANO m. INrxjmUAL PROPERTY
<img file="MX353288B_D0146.tif" />
The description and examples are not to be construed as limiting the scope of the invention to the specific embodiments and examples described herein, but rather to also cover all modifications and alternatives that involve the true scope and spirit of the invention.
’<sup>127</sup>'IMPI' Λ? Ιλ f ».íN * idad Ono ^ SBLieí rfíDCrntAL * S ^
Contents141
161 sheets
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49 members in 26 offices
Priority claims14
| Document | Office | Kind | Date |
|---|---|---|---|
| 24009209 | United States of America | P | |
| 24009209 | United States of America | P | |
| 61240092 | United States of America | – | |
| 24923109 | United States of America | P | |
| 24923109 | United States of America | P | |
| 61249231 | United States of America | – | |
| 2010047903 | United States of America | W | |
| 2010047903 | United States of America | W | |
| 61240092 | – | – | – |
| 61249231 | – | – | – |
| PCTUS2010047903 | – | – | – |
| US20090240092P | – | – | – |
| US20090249231P | – | – | – |
| WO2010US47903 | – | – | – |
Members49
| Document | Office | Kind | |
|---|---|---|---|
| CA2773033A1 | Canada | A1 | |
| CA2938650A1 | Canada | A1 | |
| WO2011029059A1 | World Intellectual Property Organization (WIPO) | A1 | |
| AU2010289326A1 | Australia | A1 | |
| IL218458D0 | Israel | D0 | |
| EP2473170A1 | European Patent Office (EPO) | A1 | |
| MX2012002731A | Mexico | A | |
| KR20120100904A | Republic of Korea | A | |
| CL2012000586A1 | Chile | A1 | |
| CN102724983A | China | A | |
| US2012276153A1 | United States of America | A1 | |
| JP2013503907A | Japan | A | |
| EP2473170A4 | European Patent Office (EPO) | A4 | |
| ZA201202434B | South Africa | B | |
| RU2012111458A | Russian Federation | A | |
| NZ598484A | New Zealand | A | |
| IN2477DEN2012A | India | A | |
| RU2563809C2 | Russian Federation | C2 | |
| AU2010289326B2 | Australia | B2 | |
| AU2015275224A1 | Australia | A1 | |
| JP2016034949A | Japan | A | |
| CA2773033C | Canada | C | |
| AU2015275224B2 | Australia | B2 | |
| US9700564B2 | United States of America | B2 | |
| JP6180012B2 | Japan | B2 | |
| AU2015275224C1 | Australia | C1 | |
| MX353288BThis record | Mexico | B | |
| CA2938650C | Canada | C | |
| US2018085376A1 | United States of America | A1 | |
| RU2015130524A | Russian Federation | A | |
| US10231975B2 | United States of America | B2 | |
| EP2473170B1 | European Patent Office (EPO) | B1 | |
| DK2473170T3 | Denmark | T3 | |
| PT2473170T | Portugal | T | |
| LT2473170T | Lithuania | T | |
| SI2473170T1 | Slovenia | T1 | |
| SMT201900440T1 | San Marino | T1 | |
| HRP20191408T1 | Croatia | T1 | |
| EP3569235A1 | European Patent Office (EPO) | A1 | |
| HUE045469T2 | Hungary | T2 | |
| US2020000817A1 | United States of America | A1 | |
| ES2739979T3 | Spain | T3 | |
| PL2473170T3 | Poland | T3 | |
| BR112012004692A2 | Brazil | A2 | |
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2 legal events, as the office reported them to INPADOC
Over the term
Point at a mark for the eventEvents
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| Grant or registrationFG | FG | |
| Transfer or rightsGB | GB |
Numbers
- Publication
- 353288
- Publication, DOCDB
- 353288
- Publication, EPODOC
- MX353288
- Application
- 2012002731
- Application, DOCDB
- 2012002731
- Application, EPODOC
- MX20120002731
Titles
- Spanish
- USO DE LEVOFLOXACINA AEROSOLIZADA PARA EL TRATAMIENTO DE FIBROSIS QUISTICA.
Classification
- CPC, 13
- A61K31/5383
- A61K9/0078
- A61K9/08
- A61K33/06
- A61K33/14
- A61K45/06
- A61P11/00
- A61P11/08
- A61P31/04
- A61P37/00
- Y02A50/30
- A61K9/12
- A61K2121/00
- IPC, 6
- A61K9 12
- A61K9 08
- A61K31 5383
- A61K33 06
- A61K45 06
- A61P11 00