Evaluation of the Pharmacokinetics and Pharmacodynamics of Liposomal Amikacin for Inhalation in Cystic Fibrosis Patients with Chronic Pseudomonal Infections Using Data from Two Phase 2 Clinical Studies

Abstract

The pharmacokinetic-pharmacodynamic (PK-PD) relationships between serum exposure measures of liposomal amikacin for inhalation (LAI) and the change in pulmonary function test (PFT) measures and number of CFU from baseline were evaluated in cystic fibrosis (CF) patients chronically infected with Pseudomonas aeruginosa. A dose of 70, 140, 280, or 560 mg of LAI or placebo was administered to CF patients once daily for 28 days. PFTs and sputum samples for microbiology were assessed on days 7, 14, 21, 28, 35 (for log 10 CFU), and 56 (for PFTs). Serum, urine, and sputum samples were collected for PK evaluation. The relationships between efficacy endpoints (relative change in forced expiratory volume in 1 s [FEV 1 {expressed in liters}] and FEV 1 % predicted and the absolute change in log 10 CFU of P. aeruginosa from baseline) and exposure measures (dose, day 1 area under the curve [AUC], dose/MIC ratio, and day 1 AUC/MIC ratio) and baseline MIC value were assessed. The serum and urine PK data were best fit by a 3-compartment model (lung, serum, and urine) with linear clearance and interoccasional variation on total and renal clearance. Significant univariable relationships between dose or day 1 AUC and the relative change in PFT measures (P < 0.017) or the absolute change in log 10 CFU from baseline (P < 0.037) on the study days were identified. Repeated-measures mixed-effects models, which showed dose-and AUC-related improvements for each efficacy endpoint (P < 0.041), predicted the observed data well. The increases in the relative change in FEV 1 and FEV 1 % predicted of 11% and 9.9%, respectively, and a 1.23-log 10 CFU reduction per 560 mg of LAI estimated on day 7 were comparable to the observed increases of 10.7% and 10.3%, respectively, and a 1.24-log 10 CFU reduction on the same day. The model-estimated PFT effects were predicted to be sustained to day 28. An additional 0.451-log 10 CFU reduction (P ‫؍‬ 0.022) was estimated on day 14 relative to day 7, with a persistence of effect predicted to day 35.

Positive Effect of Liposomal Amikacin for Inhalation on Mycobacterium abcessus in Cystic Fibrosis Patients

“…We administered 590 mg of LAI (70 mg/mL), at 1 daily dose (according to a previous pharmacokinetic/pharmacodynamic study [ 12 ]), every day for 3 months and then every other month. Each patient received clarithromycin as well, as a continuous treatment, during the entire evaluation period.…”

“…Liposomal amikacin for inhalation (LAI) is delivered using an optimized nebulizer, once a day, which allows a rapid delivery of the drug throughout the respiratory tree [ 11 ]. Pharmacological studies on humans focused on the use of such a drug against P aeruginosa infection, but mouse models showed that LAI is also effective against NTM, as much as higher concentrations of free amikacin [ 2 , 12 ]. In addition, LAI may reach high levels in alveolar macrophages, and it is associated with macrophage defects in cytokine signaling or pathogen-killing functions [ 11 ].…”

A critical review of definitions used to describe Pseudomonas aeruginosa microbiological status in patients with cystic fibrosis for application in clinical trials

“…Similar to initial Pa acquisition and eradication, studies differed widely in the crite-ria used to define chronic Pa infection. This included a wide range of timeframes required for sputum specimen positive for Pa: from 3 months [ 42 ]; six months prior to screening [43][44][45][46][47][48][49] [ 57 ] and finally 24 months prior to screening [ 58 ]. Five other studies did not specify a timeframe.…”

“…Five other studies did not specify a timeframe. The majority of studies did not specify the total number or type of samples required apart from the following specific definitions: 3 positive specimens within 2 years prior to screening and 1 within 3 months prior to screening [ 58 ]; 2 positive cultures within 12 months prior to screening (1 within the previous 3 months) or positive at screen- ing [ 49 , 52 , 53 , 55 ]. Pa was confirmed using repeated culture as part of the screening or baseline measurements in most of the studies [ 9 , 43-51 , 54 , 56 , 58 , 59 ].…”

S3-Leitlinie: Lungenerkrankung bei Mukoviszidose – Modul 2: Diagnostik und Therapie bei der chronischen Infektion mit Pseudomonas aeruginosa

“…Vor kurzem wurde zusätzlich das Fluorochinolon Levofloxacin als weitere Substanzklasse von der europäischen Arzneimittelbehörde zugelassen [75]. In naher Zukunft wird die Zulassung des Aminoglykosids Amikacin als Inhalationslösung in liposomaler Formulierung (LAI) für die chronische Infektion durch Pseudomonas aeruginosa bei CF erwartet [66,76]. Weitere Substanzen werden zurzeit für die Anwendung als inhalatives Antibiotikum entwickelt [77].…”