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 (Cmax) was < 2 mg/L and median area under the concentration-time curve (AUC0-24) 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 t1/2 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).

Conflict of interest statement

ICPD Inc received funding from Insmed Incorporated to conduct the analysis and provide general consulting to Insmed. DEG has received consulting fees and research grants from Insmed. JvI is a member of the Insmed Advisory Board. DWY and KCM are employed by Insmed. KLW has received consulting fees and research grants from Insmed.

Figures

Fig. 1

3-compartment pharmacokinetic model. Absorption (lungs), central, and urine compartments, zero-order drug administration to the lungs via nebulization occurred in the lungs, a first-order process carried the drug from the lungs to the central compartment, and the drug was removed from the body by linear elimination. C1, C2, C3 compartments 1, 2, 3; CLr renal clearance; CLt/F apparent clearance; ka absorption rate constant; Vc/F apparent volume of the central compartment

Fig. 2

Observed serum amikacin concentration versus time since last dose. Closed and open circles represent individual values for patients in CONVERT and TR02-112 studies, respectively. Amikacin concentrations that were BLQ are shown at LLOQ (i.e., 0.15 mg/L). One BLQ concentration in the TR02-112 study, observed at > 500 h after the previous dose, was excluded; it was retained in the population pharmacokinetic dataset but did not impact the model fit. BLQ below the limit of quantification; LLOQ lower limit of quantification

Fig. 3

Goodness-of-fit plots for the pooled population pharmacokinetic model (individual fitted values) versus observed data. Panels a and b show the observed versus individual fitted concentrations for serum and urine, respectively. Closed circles represent individual values for patients in CONVERT and open circles represent individual values for patients in TR02-112; the solid line indicates the line of best fit, while the dashed line represents the line of identity. Panels c and d show conditional weighted residuals versus population fitted concentrations for serum and urine, respectively; the dashed line represents a conditional weighted residual of zero. r2 coefficient of determination

Fig. 4

Sputum amikacin concentrations (CONVERT). Each circle represents individual patient data. The solid line represents a smoother through the data, assuming a 3-compartment pharmacokinetic model; the shaded region is the 90% prediction interval from a simulation assuming a % coefficient of variation of 95 for all parameters