Population Pharmacokinetic Evaluation of Amikacin Liposome Inhalation Suspension in Patients with Treatment-Refractory Nontuberculous Mycobacterial Lung Disease

• DOI: 10.1007/s13318-020-00669-7
• Publication Date: 2021-02-19T04:12:13Z
• Authors: Christopher M. Ru...; Nikolas J. Onufrak; Jakko van Ingen; David E. Griffith; Sujata M. Bhavnani; Dayton W. Yuen; Kevin C. Mange; Kevin L. Winthrop
• Keywords: Amikacin

Use of parenteral amikacin to treat refractory nontuberculous mycobacterial (NTM) lung disease is limited by systemic toxicity. A population pharmacokinetic model was developed using data pooled from two randomized trials evaluate the properties once-daily liposome inhalation suspension (ALIS) in patients with treatment-refractory NTM disease. In phase 2 (TR02-112) and 3 (CONVERT) studies, sputum cultures positive for Mycobacterium avium complex (both studies) or M. abscessus despite ≥ 6 months guideline-based therapy were treated ALIS 590 mg. Fifty-three (28 Japanese; 25 White) assessed. At baseline ≈ after daily dosing, median maximum concentration (Cmax) < mg/L area under concentration-time curve (AUC0–24) 20 mg·h/L, suggesting low exposure at both time points. Exposure estimates similar between Japanese White patients. The unchanged fraction excreted urine 10% inhaled dose throughout TR02-112 study, indicating that relatively small amounts reached circulation. Median t1/2 5.5 h. Amikacin concentrations much higher than serum, demonstrating ability achieve drug site infection. CONVERT study high 1–4 h postdose (range 242–426 μg/g) decreased 8 (median 7 μg/g). Systemic serum following administration notably lower previously reported amikacin. ClinicalTrials.gov NCT01315236 (registered March 15, 2011) NCT02344004 January 22, 2015)