Pharmacokinetic and Pharmacodynamic Evaluation of Liposomal Amikacin for Inhalation in Cystic Fibrosis Patients with Chronic Pseudomonal Infection

Abstract

The pharmacokinetics and pharmacodynamics of a novel liposomal amikacin for inhalation were evaluated in cystic fibrosis patients with chronic pseudomonas infection. Twenty-four patients from two studies received 500 mg of liposomal amikacin by inhalation once daily for 14 days. Serum, sputum, and 24-h urine samples were collected on days 1 and 14 of therapy; pulmonary function tests (PFT) and sputum for quantitative microbiology were assessed at baseline and serially for 14 days. Relationships between amikacin exposure in serum and sputum and absolute change in PFT endpoints and log 10 CFU of Pseudomonas aeruginosa from baseline on days 7 and 14 of therapy were assessed. On days 7 and 14, absolute change from baseline in forced expiratory volume in 1 s (FEV 1 ), percent predicted forced expiratory volume in 1 s (FEV 1 % predicted), and forced expiratory flow between 25 and 75% of forced vital capacity (FEF 25-75% ) increased by 0.24 (P ‫؍‬ 0.002) and 0.13 (P ‫؍‬ 0.10) liters, 7.49 (P < 0.001) and 4.38 (P ‫؍‬ 0.03), and 0.49 (P < 0.001) and 0.42 (P ‫؍‬ 0.02) liters/s, respectively. In addition, relative change from baseline in FEV 1 % predicted was 10.8% (P < 0.001) and 5.62% (P ‫؍‬ 0.073) on days 7 and 14, respectively. While significant relationships between absolute change in PFT endpoints and the ratio of serum or sputum area under the concentration-time curve to the MIC (AUC/MIC) were not observed, relationships between change in log 10 CFU and serum AUC/MIC ratio and change in log 10 CFU and absolute changes in all PFT endpoints were significant. Together, these findings likely represent drug effect and warrant the further development of liposomal amikacin for inhalation.

Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically Infected Cystic Fibrosis Patients

“…Amikacin concentrations in sputum were about 45-fold higher upon aerosolized administration of 500 mg of a liposomal formulation than after parenteral administration of 30 mg/kg of body weight; mean sputum concentrations increased ϳ3-to 5-fold from day 1 to day 14 (170,171). In supplemental material published previously (158), it was reported that mean serum concentrations as low as 1.29 g/liter and mean sputum concentrations of 2,286 g/g were recorded following aerosolized administration of 560 mg (171).…”

Design, characterization, and aerosolization of organic solution advanced spray-dried moxifloxacin and ofloxacin dipalmitoylphosphatidylcholine (DPPC) microparticulate/nanoparticulate powders for pulmonary inhalation aerosol delivery

“…[7][8][9][10][11][12][13] Targeted pulmonary delivery of antimicrobials (ie, antibacterials and antifungals) by inhalation aerosols is the subject of much recent interest in research and development, including several clinical trials. [8][9][10][11] Pulmonary liposomal aerosol delivery of antimicrobials can effectively fight infections, [14][15][16][17] and these liposomal delivery systems can be rendered into inhalable dry powder aerosols. 18 MOXI has been encapsulated in glutaraldehyde-crosslinked chitosan microspheres for intrapulmonary administration.…”

Cystic Fibrosis Therapeutics

“…Arikace is a liposomally encased preparation of amikacin, providing sustained release and rapid delivery times. Arikace has completed phase 2 trials, 2,8 reporting relative improvement in FEV 1 of 10.8% at 7 days with 500 mg inhaled once per day , and a phase 3 trial will soon be recruiting subjects with CF and P aeruginosa . 9 Another trial not specifi cally for patients with CF is also listed for subjects with nontuberculous mycobacteria and is recruiting.…”