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

Abstract

Background and Objectives 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 to evaluate the pharmacokinetic properties of once-daily amikacin liposome inhalation suspension (ALIS) in patients with treatment-refractory NTM lung disease. Methods In phase 2 (TR02-112) and phase 3 (CONVERT) studies, patients with sputum cultures positive for Mycobacterium avium complex (both studies) or M. abscessus (TR02-112) despite ≥ 6 months of guideline-based therapy were treated with once-daily ALIS 590 mg. Results Fifty-three patients (28 Japanese; 25 White) were assessed. At baseline and ≈ 6 months after daily dosing, median maximum concentration (C max ) was < 2 mg/L and median area under the concentration-time curve (AUC 0–24 ) was < 20 mg·h/L, suggesting low systemic exposure at both time points. Exposure estimates were similar between Japanese and White patients. The median unchanged amikacin fraction excreted in urine was < 10% of inhaled dose throughout the TR02-112 study, indicating that relatively small amounts reached systemic circulation. Median t 1/2 was 5.5 h. Amikacin concentrations were much higher in sputum than in serum, demonstrating the ability to achieve higher drug concentration at the site of infection. Median sputum amikacin concentrations in the CONVERT study were high at 1–4 h postdose (range 242–426 μg/g) and decreased by 8 h (median 7 μg/g). Conclusions Systemic exposure to amikacin in serum and urine following once-daily ALIS administration in patients with treatment-refractory NTM lung disease was notably lower than that previously reported for parenteral amikacin. Trial registration ClinicalTrials.gov NCT01315236 (registered March 15, 2011) and NCT02344004 (registered January 22, 2015) Supplementary Information The online version contains supplementary material available at 10.1007/s13318-020-00669-7.

The role of amikacin in the treatment of nontuberculous mycobacterial disease

“…ALIS treatment yields low systemic exposures, with median C max values <2 mg/L and median AUC 0-24 values of <20 mg•h/L in serum. Sputum amikacin concentrations were in the range of 242-426 µg/g sputum, 1 to 4 hours post dose [68]. These concentrations dropped to a median of 7 µg/g sputum in the following 8 hours [68].…”

“…Sputum amikacin concentrations were in the range of 242-426 µg/g sputum, 1 to 4 hours post dose [68]. These concentrations dropped to a median of 7 µg/g sputum in the following 8 hours [68].…”

Nontuberculous mycobacterial lung disease caused by Mycobacterium avium complex - disease burden, unmet needs, and advances in treatment developments

“…In an in vitro study, ALIS penetrated MAC biofilms and displayed concentration-dependent killing of MAC [105]. ALIS administration also results in low systemic exposure to amikacin, with less than 10% of an ALIS dose reaching the systemic circulation [108].…”

Liposomal drug delivery to manage nontuberculous mycobacterial pulmonary disease and other chronic lung infections

“…It is known that amikacin ototoxicity is associated with cumulative exposure and duration of treatment with AUC values that exceed 50 mg•L −1 •h [122,123,130]. Population pharmacokinetic analysis of ALIS in the phase 3 CONVERT and phase 2 study demonstrated a relatively low exposure to amikacin, with once-daily dosing of ALIS of <2 mg•L −1 and a median AUC from 0-24 h of <20 mg•L −1 •h [132]. The median AUC from day 1 to day 168 (6 months) is within <10%, suggesting that systemic exposure remains stable and similar regardless of treatment duration and is notably lower than that seen with parenteral amikacin [132].…”

“…Population pharmacokinetic analysis of ALIS in the phase 3 CONVERT and phase 2 study demonstrated a relatively low exposure to amikacin, with once-daily dosing of ALIS of <2 mg•L −1 and a median AUC from 0-24 h of <20 mg•L −1 •h [132]. The median AUC from day 1 to day 168 (6 months) is within <10%, suggesting that systemic exposure remains stable and similar regardless of treatment duration and is notably lower than that seen with parenteral amikacin [132]. Given the inhaled nature of ALIS, the risks of systemic exposure are perhaps not surprising, and confirm early data where deposition of ALIS was confined primarily to the lung with limited transfer into the bloodstream outside of the lung [67].…”