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WO2008137917A1 - Procédé de traitement d'infections bactériennes avec des formulations antibactériennes - Google Patents

Procédé de traitement d'infections bactériennes avec des formulations antibactériennes Download PDF

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Publication number
WO2008137917A1
WO2008137917A1 PCT/US2008/062868 US2008062868W WO2008137917A1 WO 2008137917 A1 WO2008137917 A1 WO 2008137917A1 US 2008062868 W US2008062868 W US 2008062868W WO 2008137917 A1 WO2008137917 A1 WO 2008137917A1
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WIPO (PCT)
Prior art keywords
day
antibiotic formulation
days
amikacin
antibiotic
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PCT/US2008/062868
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English (en)
Inventor
Frank G. Pilkiewicz
Vladimir Malinin
Xingong Li
Renu Gupta
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Transave, Inc.
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Priority to US12/250,412 priority Critical patent/US9114081B2/en
Publication of WO2008137917A1 publication Critical patent/WO2008137917A1/fr
Priority to US13/480,246 priority patent/US9119783B2/en
Priority to US13/566,707 priority patent/US9333214B2/en
Priority to US14/809,127 priority patent/US9724301B2/en
Priority to US14/809,128 priority patent/US9737555B2/en
Priority to US15/638,548 priority patent/US10064882B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant

Definitions

  • the present invention relates to a method of treating a bacterial infection in a human comprising administering to a human in need thereof an effective amount of an antibiotic formulation by inhalation once every day or once every greater time interval.
  • the antibiotic formulation is a lipid based antibiotic formulation.
  • the antibiotic formulation is a liposomal antibiotic formulation.
  • the antibiotic is an aminoglycoside.
  • the antibiotic is amikacin.
  • the amount of antibiotic formulation is 5 to 2,500 mg.
  • the amount of antibiotic formulation is 250 to 1,500 mg.
  • the amount of antibiotic formulation is 500 to 1,000 mg.
  • the antibiotic formulation is administered once every day. In a further embodiment, the antibiotic formulation is administered once every two days. In a further embodiment, the antibiotic formulation is administered once every three days. In a further embodiment, the antibiotic formulation is administered once every day for 5 days to 6 months. In a further embodiment, the antibiotic formulation is administered once every day for 5 days to 3 months. In a further embodiment, the antibiotic formulation is administered once every day for 5 days to 2 months. In a further embodiment, the antibiotic formulation is administered once every day for 5 days to 1 month. In a further embodiment, the antibiotic formulation is administered once every day for 5 days to 2 weeks. In a further embodiment, the antibiotic formulation is administered once every day for a week.
  • the antibiotic formulation is administered once every day for a week followed by a week of no administration, wherein this cycle is repeated more than once. In a further embodiment, the antibiotic formulation is administered once every day for 14 days followed by 14 days of no administration, wherein this cycle is repeated more than once. In a further embodiment, the antibiotic formulation is administered once every day for 28 days followed by 28 days of no administration, wherein this cycle is repeated more than once.
  • the antibiotic is amikacin and the amount of antibiotic formulation is 5 to 2,500 mg administered once every day for 5 days to 3 months.
  • the lipid based or liposomal antibiotic formulation comprises a lipid selected from the group consisting of egg phosphatidylcholine (EPC), egg phosphatidylglycerol (EPG), egg phosphatidylinositol (EPI), egg phosphatidylserine (EPS), phosphatidylethanolamine (EPE), phosphatidic acid (EPA), soy phosphatidylcholine (SPC), soy phosphatidylglycerol (SPG), soy phosphatidylserine (SPS), soy phosphatidylinositol (SPI), soy phosphatidylethanolamine (SPE), soy phosphatidic acid (SPA), hydrogenated egg phosphatidylcholine (HEPC), hydrogenated egg phosphatidylglycerol (HEPG), hydrogenated egg phosphatidylinositol (HEPI), hydrogenated egg phosphatidylserine
  • EPC egg
  • the lipid based or liposomal antibiotic formulation comprises a phospholipid and a sterol. In a further embodiment, the lipid based or liposomal antibiotic formulation comprises DPPC and cholesterol. In a further embodiment, the lipid based or liposomal antibiotic formulation comprises DPPC and cholesterol in a 2 to 1 ratio by weight.
  • the antibiotic is amikacin; the amount of antibiotic formulation is 5 to 2,500 mg administered once every other day for a week to 3 months, and the lipid based or liposomal antibiotic formulation comprises DPPC and cholesterol in a 2 to 1 ratio by weight.
  • Figure 1 depicts mass distribution of Liposomal Amikacin nebulizate collected on impactor stages as a function of cutoff diameter.
  • the three Liposomal Amikacin lots of Table 15 legend (designated as 1, 2, and 3) were used with the eFlow nebulizer and ACI system (solid symbols) or the LC Star nebulizer and NGI system (open symbols).
  • Figure 2 depicts reduction in the LogioCFU/Lungs of Rats after Inhalation of Liposomal Amikacin 75 mg/mL or Tobramycin
  • the symbols represent the LogioCFU/lungs of each rat 18 days after the instillation of PA3064 in agar beads and 3 days after the last inhalation session of saline or one of the above antibiotics.
  • the values at 2.0 Logio CFU represent the lower limit of detection of bacteria in the lung in the method.
  • the bar represents the mean of each group.
  • the means and standard deviations and two-tail t-test results were calculated using Excel software by
  • Figure 3 depicts reduction in the LogioCFU / lungs of rats after Inhalation of Liposomal Amikacin and Tobramycin for 28 days. Equivalent doses of the above antibiotics were given by inhalation therapy but on different schedules. Tobramycin was given BID daily for a total of 104 min per day for 28 days. Liposomal Amikacin was given once daily for 80 min for 28 days (QlDx28) as was saline. Liposomal Amikacin was also given once daily for 160 min every other day for 28 days (Q2Dxl4) or once daily for 160 min for 14 consecutive days (Q IDX 14) then just observed until the rats were euthanized. The symbols represent the LogioCFU/ lungs of each rat 35 days after the instillation of P. aeruginosa 3064 in agar beads. The means and standard deviations and two-tail t-test were calculated using Excel software by Microsoft).
  • an element means one element or more than one element.
  • pulmonary distress refers to any disease, ailment, or other unhealthy condition related to the respiratory tract of a human. Generally pulmonary distress results in difficulty of breathing.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • substituted is also contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above.
  • the permissible substituents may be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • hydrocarbon is contemplated to include all permissible compounds having at least one hydrogen and one carbon atom.
  • permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds that may be substituted or unsubstituted.
  • treating is art-recognized and refers to curing as well as ameliorating at least one symptom of any condition or disease.
  • prophylactic or therapeutic treatment is art-recognized and refers to administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate or maintain the existing unwanted condition or side effects therefrom).
  • a "patient,” “subject” or “host” to be treated by the subject method may mean either a human or non-human animal.
  • mammals include humans, primates, bovines, porcines, canines, felines, and rodents (e.g., mice and rats).
  • bioavailable is art-recognized and refers to a form of the subject invention that allows for it, or a portion of the amount administered, to be absorbed by, incorporated to, or otherwise physiologically available to a subject or patient to whom it is administered.
  • pharmaceutically-acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds, including, for example, those contained in compositions of the present invention.
  • pharmaceutically acceptable carrier refers to a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically-acceptable material such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the subject composition and its components and not injurious to the patient.
  • materials which may serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
  • compositions described herein include compositions which otherwise correspond thereto, and which have the same general properties thereof, wherein one or more simple variations of substituents or components are made which do not adversely affect the characteristics of the compositions of interest.
  • the components of the compositions of the present invention may be prepared by the methods illustrated in the general reaction schema as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are in themselves known, but are not mentioned here.
  • Lipid based or liposomal aminoglycoside, such as amikacin, formulations for inhalation are sustained-release formulations of aminoglycosides encapsulated inside nanoscale liposomal carriers designed for administration via inhalation. It is hypothesized that the sustained-release targeting of high concentrations of amikacin in the lungs and bio film penetration properties of this formulation will have several advantages over inhaled tobramycin in treating CF subjects with chronic infection caused by P. aeruginosa. These advantages include: 1. The ability to attain a prolonged antibiotic effect of amikacin in the lung by achieving high concentrations and a prolonged half life due to sustained release.
  • Amikacin is a semisynthetic aminoglycoside with a unique resistance to aminoglycoside inactivating enzymes. Consequently, some P. aeruginosa strains which are resistant to tobramycin will remain susceptible to amikacin.
  • Amikacin has less binding affinity than other aminoglycosides for megalin, the transporter responsible for renal cortical aminoglycoside accumulation, and thus inherently has a lower potential for nephrotoxicity.
  • Liposomal Amikacin administered at 120 mg/kg once a day for 14 days was as effective as Tobramycin 60 mg/kg/day (administered twice a day) for 28 days, which suggests a higher AUC and possibly a prolonged post-antibiotic effect with Liposomal Amikacin at 120 mg/kg dosed once per day (see Example 3).
  • Liposomal Amikacin via inhalation in the animal model resulted in increased lung (AUC) above the MIC of the bacteria, and demonstrated sustained therapeutic effect, with a reduced frequency, and duration of dosing as compared to Tobramycin.
  • AUC lung
  • the preclinical data for Liposomal Amikacin appear supportive of the hypothesis that this specific formulation may be advantageous over other inhalation products that are hindered by a rapid clearance from lung tissue, necessitating frequent dosing (Geller, Pitlick et al. 2002), which poses a burden for patients and might limit patient compliance.
  • This, along with the safety pharmacology profile of the molecule is supportive of further development of this formulation in the clinic.
  • Transave, Inc. has developed a sustained release targeting formulation of amikacin encapsulated inside nanoscale liposomal carriers designed for administration via inhalation (Liposomal Amikacin). Using data from a human clinical Phase lb/2a study in which CF patients who were chronically infected with P.
  • aeruginosa received multiple doses of Liposomal Amikacin 50 mg/ml, the objectives of the analyses described herein were three-fold: (1) to use population pharmacokinetic (PK) modeling to characterize amikacin systemic exposure, including approximate systemic bioavailability; (2) to characterize the disposition of liposomal amikacin in sputum; and 3) to characterize the pharmacokinetic-pharmacodynamic (PK- PD) relationship between change in forced expiratory volume in one second (FEVi), change in percent predicted forced expiratory volume in one second (FEVi % predicted), forced expired flow between 25-75% of forced vital capacity (FEF 2 5-75%), and forced vital capacity (FVC), in P. aeruginosa colony forming units (CFU) relative to baseline at Days 7 and 14, and amikacin exposure.
  • PK population pharmacokinetic
  • FEVi change in forced expiratory volume in one second
  • FEVi % predicted change in percent predicted forced expiratory volume in one second
  • FVC forced
  • PK analysis were obtained from two human clinical Phase lb/2a studies (103 and 104) in which CF patients, chronically infected with P. aeruginosa, were administered a total of 500 mg of Liposomal Amikacin daily (as two 20 minute sessions with a 5 minute rest period in between) for 14 days.
  • Amikacin serum samples were obtained pre-dose, and 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Days 1 and 14, while urine samples were collected over 6 hour intervals on Day 1 and Day 14 for a period of 24 hours.
  • Sputum samples were also collected on Day 1 and Day 14, soon after the dose was administered, between 4 and 6 hours after dosing and prior to dose administration on the following day, as well as on Days 14, 21, and 28.
  • Serum, sputum and urine samples were assayed for amikacin using Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS).
  • Pulmonary function tests were carried out during screening from Day -14 to 0) and at baseline (i.e., prior to dose administration on Day 1) and on Day 1, 7, 14, 21, 28, 35, and 42. Sputum samples for microbiology were also collected at baseline and on each of these days. Additional PFTs were carried out 1.5 hours and 3 hours post-dose on Day 1 and Day 14.
  • the data were fit by candidate PK models, using Monte Carlo Parametric Expectation Maximization (MC-PEM), as is implemented in S-ADAPT 1.53, initially fitting the plasma concentrations, then co-modeling the serum and urine data. Model discrimination was based on the fit of the data and change in objective function.
  • the 24 hour area under the curve (AUC) at steady state for serum amikacin values were calculated using the post-hoc parameter estimates from the final population PK model.
  • Covariate relationships between patient demographics and individual post-hoc parameters were assessed first graphically, then by means of statistical models created using SYSTAT ® 11 (SYSTAT Software, Inc., Richmond, CA). Sputum AUC values from 0 to 24 hours on Day 1 and Day 14 were obtained using the linear trapezoidal rule.
  • Dependent variables for the PK-PD analysis included the change in PFT values for FEVi, FEVi % predicted, FEF25_75 ⁇ > /0 and FVC, on Day 7 and 14 relative to baseline (i.e., prior to dose administration on Day 1) and the change in logio CFU on each of these days relative to baseline.
  • Independent variables evaluated included the ratio of the average 24 hour AUC for serum and sputum to the baseline minimum inhibitory concentration (MIC), AUC:MIC ratio for P. aeruginosa. The average 24 hour serum and sputum AUC was computed by taking the average of the Day 1 and Day 14 AUC values.
  • the goodness of fit for observed versus Bayesian post-hoc individual fitted serum concentration data was excellent, with an overall r 2 of 0.98. As evidenced by an overall r 2 of 0.38 for observed versus individual fitted urine data, the goodness of fit for urine data was poor.
  • the post-hoc covariate analysis, using generalized linear modeling (GLM) revealed a significant relationship between height and gender and Day 14 estimates of CLt/F and Vc/F.
  • the post-hoc renal clearances obtained appeared to be falsely low, which was likely due to incomplete urine collection and poor documentation.
  • the AUC values for the serum and sputum data are shown in Tables 2 and 3, respectively. Median AUC values for sputum were 286 and 978 fold greater than the median AUC values for serum on Day 1 and Day 14, respectively. As evidenced by the higher CV% values, greater variability was evident in sputum (117% on Day 1 and 91.2% on Day 14) compared to serum AUC (51.9% on Day 1 and 42.4% on Day 14) values. Table 2. Summary of serum AUC values 1 - All patients
  • Liposomal amikacin for inhalation pharmacokinetics was best described using a two-compartment model (one absorption site, the lung, and one central compartment) with zero-order input into the lung, a first-order process from the lungs to the central compartment and linear elimination.
  • the median AUC values for sputum were 286 and 978 fold greater than the median AUC values for serum on Day 1 and Day 14, respectively.
  • the high degree of variability associated with sputum AUC values precluded further insight into the pulmonary bioavailability of liposomal amikacin for inhalation.
  • Mean changes in PFT values on Day 7 relative to baseline were statistically significant for all PFT endpoints. Similar such results were evident for FEVi % predicted and FEF25-750 /0 on Day 14 for relative to baseline and for FEVi, FEVi % predicted and FEF 25 _ 75 O /O on Day 21 relative to baseline.
  • correlations between change in PFT values from baseline and sputum or serum AUC:MIC ratio were not statistically significant when either changes on Day 7 or 14 relative to baseline were evaluated.
  • the mean MIC ( ⁇ g/mL) was 8 (range 1.5-16) and in Study 104, the mean MIC was 41 ⁇ g/mL (range 8- 192).
  • the patients enrolled in Study 104 had prior experience with inhalation antibiotics, and per protocol, were permitted to resume treatment with TOBI ® /Colistin after Day 28 of the study.
  • the patients in Study 103 were na ⁇ ve to inhalation antibiotics, and did not receive additional inhalation antibiotics during the follow-up period.
  • the 500 mg dose of Liposomal Amikacin (50 mg/mL) was well tolerated, and in select patients improved pulmonary function and decreased the density of P. aeruginosa in sputum.
  • the details of patient demographics for Studies 103 and 104 (combined) are shown in Table 6.
  • Quantitative culture of sputum samples and subsequent amikacin susceptibility testing of each morphologically distinct P. aeruginosa were performed.
  • the MIC of amikacin for the isolates with the highest MIC cultured from each subject at screening and Day 14 was documented.
  • the density (CFU per gram of sputum) of P. aeruginosa in sputum was calculated as the log 10 value for the sum of all morphotypes.
  • Study 104 was conducted in a population of CF patients who were infected with P. aeruginosa, and were inhalation antibiotic treatment experienced. In these patients, the administration of Liposomal Amikacin 500 mg q.d. for 2 weeks did not show any significant change in P. aeruginosa density during the study (p-values >0.297 for change from Day 1). The proportion of patients with mucoid P. aeruginosa remained constant throughout the study. No statistically significant changes in FEVi, FEVi % predicted, FVC, and FEF (25-75%) were observed after administration of Liposomal Amikacin 500 mg. However, trends suggesting improvement in FEVi % predicted, FVC, and FEF(25_75%) were observed at Day 7, Day 14 (end of treatment), and Day 15. Integrated Efficacy Summary: Studies 103 and 104
  • PK data confirm minimal systemic drug levels, and high sputum levels of drug, and pharmacodynamic modeling estimates long elimination half life presumably due to slow release from liposomes.
  • Drug was administered using a PARI LC Star nebulizer, over a period of two 20-minute inhalation sessions with a 5 minute rest period between sessions.
  • Study 103 There were 13 patients enrolled in Study 103 and 11 patients in Study 104. Patient demographics were similar, with the exception of Pseudomonas MICs at baseline, and history of prior exposure to inhalation antibiotics.
  • the mean MIC ( ⁇ g/mL) was 8 (range 1.5-16) and in Study 104 the mean MIC was 41 ⁇ g/mL (range 8-192).
  • the patients enrolled in study 104 had prior experience with inhalation antibiotics, and per protocol, were permitted to resume treatment with TOBI ® /Colistin after Day 28 of the study.
  • the patients in Study 103 were na ⁇ ve to inhalation antibiotics, and did not receive additional inhalation antibiotics during the follow-up period.
  • the treatment was safe and well tolerated, with the most frequent AEs being dyspnea and headache of mild to moderate severity.
  • Study 103 Liposomal Amikacin 50 mg/mL formulation was well tolerated at a daily dose of 500 mg for 14 days in a group of 13 CF patients with chronic P. aeruginosa infection. Twenty-one AEs were experienced by 9 of the 13 patients. AEs reported by more than a single subject included: productive cough, dysgeusia, myalgia, and hemoptysis. All AEs were judged moderate or mild in intensity. No subjects were discontinued from the study due to an AE.
  • Study 104 Thirty-two AEs were experienced by 10 of the 11 patients. Adverse events experienced by more than one subject included headaches, dyspnea, rales, musculoskeletal chest pain, and cough. Abnormalities in safety parameters were mostly related to the underlying CF condition and were present at baseline. Treatment-emergent abnormalities were infrequent and transient. One subject experienced viral bronchopneumonia that started 9 days after the end of treatment with the study drug, and was reported as an SAE. This resolved within 5 months. The SAE was deemed to be doubtfully related to the study drug by the investigator. All adverse events were judged moderate or mild in intensity, except for AEs associated with the episodes of viral bronchopneumonia. A summary of AE's from the human clinical phase l/2a studies is found in Table 12.
  • Liposomal Amikacin appeared to be safe and well tolerated up to the highest inhaled dose level (500 mg) in this group of CF patients with chronic P. aeruginosa infection.
  • Infection with P. aeruginosa is associated with increased morbidity and mortality in cystic fibrosis subjects.
  • the aggressive use of oral, intravenous, and aerosolized antibiotics has contributed to increased longevity of these subjects over the past 3 decades.
  • inhaled antibiotics specifically inhaled tobramycin, are indicated for the treatment of established infections of P. aeruginosa in CF subjects.
  • Use of tobramycin 300 mg inhaled twice a day on alternating months has been shown to increase FEVi % predicted, decrease the density of P. aeruginosa in sputum, decrease hospitalizations, and reduce the need for intravenous antibiotics (Ramsey, Pepe et al. 1999).
  • Liposomal Amikacin technology offers two advantages over inhaled tobramycin: the first being decreased frequency of dosing (i.e., 1 time per day or less versus 2 times per day), and the second being sustained, high local drug concentrations with concomitant low systemic levels of drug.
  • the lipids used in the Liposomal Amikacin formulation are the same as the endogenous surfactant layer of human lung and are not expected to elicit any adverse reaction.
  • the single most prevalent compound in pulmonary surfactant is the disaturated phospholipid, dipalmitoylphosphatidylcholine (DPPC), which is crucial for surface tension lowering.
  • DPPC dipalmitoylphosphatidylcholine
  • the ratio of DPPC: Amikacin in Liposomal Amikacin, 50 mg/ml is 1.0 w:w.
  • DPPC dipalmitoylphosphatidylcholine
  • liposomes for the inhalational administration of drugs has been studied in both rodents and humans and has demonstrated few adverse effects (Taylor, Taylor et al. 1989; Thomas, Myers et al. 1991; Myers, Thomas et al. 1993; Vidgren, Waldrep et al. 1994; Hung, Whynot et al. 1995; Gilbert, Knight et al. 1997; Skubitz and Anderson 2000; Landyshev Iu, Grigorenko et al. 2002; Ten, Anderson et al. 2002). Further, liposomal formulations have been prepared for a number of drugs in these studies, and in many cases it is has been shown that the inhaled liposomal drug has a longer half life in the lung than its free drug (non-liposomal formulation).
  • alveolar foamy macrophage accumulation in the lung was the principal finding.
  • the macrophage accumulation was considered a normal clearance response of the lung to aerosolised materials and not a direct toxic effect of Liposomal Amikacin.
  • the macrophage accumulation showed evidence of reversibility.
  • alveolar macrophages retained their normal function following daily inhalation of Liposomal
  • Liposomal Amikacin at approximately 50 mg/kg for 14 days in rats.
  • Liposomal Amikacin showed no evidence of genotoxicity .
  • Liposomal Amikacin was tested up to cytotoxic levels (Ames assay), at concentrations limited by precipitation (chromosome aberration assay in Chinese hamster ovary cells), or up to the testing limit of 5,000 ⁇ g/mL (mouse lymphoma assay).
  • Nonclinical pharmacokinetics have demonstrated that the AUC (0-48 hr) of amikacin in the lungs of rats that received a 60 mg/kg dose of Liposomal Amikacin via nebulization, was five-fold higher than the AUC of tobramycin in the lungs of rats that received an equal dose of tobramycin by inhalation.
  • High levels of amikacin were sustained in the lung (>250 ⁇ g/mL through 150 hr), suggesting a depot effect.
  • lung levels of tobramycin were undetectable within 6 hours of cessation of administration.
  • the safety pharmacology profile of Liposomal Amikacin is currently derived from GLP general toxicology studies in rats and dogs.
  • a 30-day inhalation toxicology study in dogs at Liposomal Amikacin doses up to approximately 30 mg/kg there were no indications of adverse effects on respiratory or electrocardiographic parameters.
  • this study and a companion 30-day inhalation toxicology study in rats there were no substantive in-life changes and no drug-related histopathologic changes in any organ except the lung (both species) and upper respiratory tract (rats); this is likely related to the very low plasma levels of Amikacin in both species following inhalation dosing with Liposomal Amikacin.
  • Liposomal Amikacin The pharmacodynamic effect of Liposomal Amikacin was evaluated in vivo in a rat model of chronic pulmonary infection with Pseudomonas (Cash, Woods et al. 1979).
  • 14 days pseudomonas infection model it was noted that 60 mg/kg of Liposomal Amikacin (75 mg/mL) administered every other day for 14 days (Q2D x 7), which effectively delivered half the cumulative dose of aminoglycoside than the other groups, was as effective as 60 mg/kg of Liposomal Amikacin (given once per day), and tobramycin (given twice per day) daily for 14 days.
  • Liposomal Amikacin via inhalation resulted in increased lung concentrations (AUC) several fold above the MIC of the bacteria, with the potential to provide a sustained therapeutic effect with a reduced frequency and duration of dosing as compared to Tobramycin.
  • AUC lung concentrations
  • Drug was administered using a PARI LC Star nebulizer, over a period of two 20-minute inhalation sessions with a 5 minute rest between periods.
  • the mean MIC ( ⁇ g/mL) was 8 (range 1.5-16) and in Study 104 the mean MIC was 41 ⁇ g/mL (range 8-192).
  • the patients enrolled in study 104 had prior experience with inhalation antibiotics, and per protocol, were permitted to resume treatment with TOBI ® /Colistin after Day 28 of the study.
  • the patients in Study 103 were na ⁇ ve to inhalation antibiotics, and did not receive additional inhalation antibiotics during the follow-up period. Overall, the treatment was safe and well tolerated, with the most frequent AEs being dyspnea and headache of mild to moderate severity. There were 12/49 (24.4%) AEs reported as possibly or probably related to Liposomal Amikacin.
  • the effect at day 14 was a 126 mL increase from baseline in FEVl, which was not statistically significant.
  • Liposomal Amikacin is formulated for the treatment of pulmonary gram-negative bacterial infections, and pulmonary mycobacterial infections.
  • the current focus of the development program is for the treatment of CF subjects with P. aeruginosa infections.
  • CF occurs primarily in individuals of central and western European origin. In the United States, the median age at death has increased from 8.4 years of age in 1969 to 14.3 years of age in 1998. The mean age of death has increased from 14 years in 1969 to 32.4 years of age in 2003 (Cystic Fibrosis Foundation). A major contributor to the significant increase in life expectancy is improved antibiotic treatment of chronic respiratory tract infections in CF subjects (Goss and Rosenfeld 2004) as well as improved nutrition and earlier diagnosis.
  • a major factor in the respiratory health of CF subjects is acquisition of chronic Pseudomonas aeruginosa infections.
  • the infection rate with P. aeruginosa increases with age and by age 18 years, 80% of CF subjects in the U.S. are infected.
  • the difficulties treating this infection are multifactorial, including poor penetration of antibiotics into sites of infection including mucus plugs, inactivation of antibiotics by CF sputum, growth of bacteria in a bio film, changes in phenotype including conversion to a mucoid form of P. aeruginosa, and emergence of multi-drug resistance (Chmiel and Davis 2003; Gibson, Burns et al. 2003).
  • the cornerstone of pulmonary therapy is optimizing treatment of P. aeruginosa as infection with this pathogen is associated with a poor clinical outcome (Doring, Conway et al. 2000; Chmiel and Davis 2003; Gibson, Burns et al. 2003; Gibson, Emerson et al. 2003
  • One of the current approaches to management of chronic P. aeruginosa infection in humans with CF includes the use of suppressive therapy with inhaled tobramycin (TOBI ® ).
  • Inhaled tobramycin 300 mg, administered twice a day for cycles of 28 days followed by 28 days off drug has been shown to reduce P. aeruginosa colony counts, increase FEVi % predicted, reduce hospitalizations, and decrease antibiotic use (Ramsey, Pepe et al. 1999).
  • patients have to be dosed twice a day for approximately 15-20 minute inhalation periods per dose.
  • Amikacin was encapsulated in liposomes composed of dipalmitoylphoshatidylcholine (DPPC) and cholesterol, at a targeted lipid-to-drug ratio of 0.6-0.7:1 (w/w).
  • DPPC dipalmitoylphoshatidylcholine
  • the quantitative formula for liposomal amikacin, 70 mg/mL is presented in Table 14.
  • Liposomal amikacin was made using an aseptic process that involves the preparation of three solutions, sterile filtration of the solutions into a sterilized reactor utilizing in-line mixing, followed by diaf ⁇ ltration and concentration of the resulting liposomal suspension to form the final product as described below.
  • Diafiltration is initiated upon the completion of the infusion and initial concentration. Diafiltration occurs at approximately 30 0 C via the same diafiltration cartridge used for the Infusion/Initial Concentration (2).
  • the bulk solution is maintained at a constant mass while 1.5% Sodium Chloride Solution is added to the reactor.
  • the aerosol properties of Liposomal Amikacin produced from the eFlow 4OL are shown in Table 15.
  • the mass median aerodynamic diameter (MMAD) values for the eFlow are ⁇ 0.5 ⁇ m larger.
  • the actual size dependent mass distributions from both ACI (with eFlow) and NGI (with LC Star) cascade impactors for nebulized Liposomal Amikacin are shown in Figure 1. Aerosol from the eFlow/ ACI measurements was slightly narrower in size distribution than that from the LC Star/NGI. This difference is reflected in the lower mean geometric standard deviation (GSD) (1.66 versus 1.99) which is a measure of the width of the distribution around the MMAD, see values in Table 15.
  • GSD geometric standard deviation
  • the Andersen cascade impactor was used at a flow rate of 28.3 L/min, 18 0 C, and 50% humidity.
  • the NGI impactor was used at a flow rate of 15L/min and 5 0 C to achieve >60% humidity. ⁇ Percent mass of the nominal drug dose that is less than 5 ⁇ m in diameter.
  • Liposomal Amikacin was studied using a model for chronic pulmonary infection (Cash, Woods et al. 1979) where P. aeruginosa, embedded in an agarose bead matrix, was instilled in the trachea of rats.
  • This mucoid Pseudomonas animal model was developed to resemble the chronic Pseudomonas infections seen in CF patients (Cantin and Woods 1999).
  • Rat lungs were inoculated with 10 4 CFUs of a mucoid P. aeruginosa strain (mucoid strain 3064) originally isolated from a CF patient.
  • Liposomal Amikacin 75 mg/mL was administered by inhalation once daily for 14 doses (QlD x 14) or every other day for 7 doses (Q2D x 7) (6 mg/kg per dose).
  • tobramycin was administered by inhalation BID for 14 days (30 mg/kg per dose for a total of 60 mg/kg daily).
  • Q2D x 7 Liposomal Amikacin (75 mg/mL) administered every other day for 14 days (Q2D x 7), which effectively delivered half the cumulative dose of aminoglycoside, was as effective as the daily dosing regimen in this model.
  • Liposomal Amikacin administered at 120 mg/kg once a day for 14 days was as effective as tobramycin 60 mg/kg/day (administered twice a day) for 28 days. This result suggests a higher AUC and possibly a prolonged post-antibiotic effect with Liposomal Amikacin at 120 mg/kg.

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Abstract

L'invention concerne, en partie, un procédé de traitement d'une infection bactérienne chez un être humain comprenant l'administration à un être humain qui en a besoin d'une quantité efficace d'une formulation antibiotique de lipide par inhalation une fois par jour ou une fois par intervalle de temps plus important. Dans certains modes de réalisation, la formulation est une formulation antibiotique liposomale. Dans certains modes de réalisation, l'antibiotique est un aminoglycoside, tel que l'amikacine.
PCT/US2008/062868 2007-05-07 2008-05-07 Procédé de traitement d'infections bactériennes avec des formulations antibactériennes WO2008137917A1 (fr)

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US12/250,412 US9114081B2 (en) 2007-05-07 2008-10-13 Methods of treating pulmonary disorders with liposomal amikacin formulations
US13/480,246 US9119783B2 (en) 2007-05-07 2012-05-24 Method of treating pulmonary disorders with liposomal amikacin formulations
US13/566,707 US9333214B2 (en) 2007-05-07 2012-08-03 Method for treating pulmonary disorders with liposomal amikacin formulations
US14/809,127 US9724301B2 (en) 2007-05-07 2015-07-24 Methods of treating pulmonary disorders with liposomal amikacin formulations
US14/809,128 US9737555B2 (en) 2007-05-07 2015-07-24 Method of treating pulmonary disorders with liposomal amikacin formulations
US15/638,548 US10064882B2 (en) 2007-05-07 2017-06-30 Methods of treating pulmonary disorders with liposomal amikacin formulations

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US9114081B2 (en) 2007-05-07 2015-08-25 Insmed Incorporated Methods of treating pulmonary disorders with liposomal amikacin formulations
US9119783B2 (en) 2007-05-07 2015-09-01 Insmed Incorporated Method of treating pulmonary disorders with liposomal amikacin formulations
EP2852391A4 (fr) * 2012-05-21 2015-10-28 Insmed Inc Systèmes de traitement d'infections pulmonaires
WO2016061561A1 (fr) * 2014-10-16 2016-04-21 Natureza, Inc. Formulations ayant une activité anti-inflammatoire et une activité antimicrobienne contre les bactéries gram positif
US9333214B2 (en) 2007-05-07 2016-05-10 Insmed Incorporated Method for treating pulmonary disorders with liposomal amikacin formulations
US9402845B2 (en) 2005-12-08 2016-08-02 Insmed Incorporated Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof
US9827317B2 (en) 2002-10-29 2017-11-28 Insmed Incorporated Sustained release of antiinfectives
US9895385B2 (en) 2014-05-15 2018-02-20 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US9925205B2 (en) 2007-05-04 2018-03-27 Insmed Incorporated Compositions of multicationic drugs for reducing interactions with polyanionic biomolecules and methods of use thereof
US10124066B2 (en) 2012-11-29 2018-11-13 Insmed Incorporated Stabilized vancomycin formulations
US11351134B2 (en) 2017-08-11 2022-06-07 Natureza Products, Inc. Small molecule agents, compositions, and formulations, for internal use, displaying inhibitory activity against gram-positive and/or gram-negative organisms
US11571386B2 (en) 2018-03-30 2023-02-07 Insmed Incorporated Methods for continuous manufacture of liposomal drug products

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US9511082B2 (en) 2005-12-08 2016-12-06 Insmed Incorporated Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof
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