Population Pharmacokinetic Analysis of Bedaquiline-Clarithromycin for Dose Selection Against Pulmonary Nontuberculous Mycobacteria Based on a Phase 1, Randomized, Pharmacokinetic Study.

Based on in vitro profile of bedaquiline against mycobacterial species, it is being investigated for clinical efficacy against pulmonary nontuberculous mycobacteria (PNTM). Being a cytochrome P450 (CYP) 3A substrate, pharmacokinetic interactions of bedaquiline are anticipated with clarithromycin (a CYP3A inhibitor), which is routinely used in PNTM treatment. This Phase 1, randomized, crossover study assessed the impact of steady-state clarithromycin (500 mg every 12 hours; 14 days) on the pharmacokinetics of bedaquiline and its metabolite (M2) after single-dose bedaquiline (100 mg; n  =  16). Using these data, population pharmacokinetic modeling and simulation analyses were performed to determine the effect of clarithromycin on steady-state bedaquiline exposure. Although no effect was observed on maximum plasma concentration (Cmax ) of bedaquiline and time to achieve Cmax (tmax ), its mean plasma exposure increased by 14% after 10 days of clarithromycin coadministration, with slower formation of M2. Simulations showed that bedaquiline plasma trough concentration at steady-state was higher (up to 41% until Week 48) with clarithromycin coadministration as compared to its monotherapy (400 mg once daily [qd] for 2 weeks, followed by 200 mg thrice a week for 46 weeks; reference regimen). The overall exposure of a simulated bedaquiline regimen (400 mg qd for 2 weeks, followed by 200 mg twice a week [biw] for 46 weeks) with clarithromycin was comparable (<15% difference) to the monotherapy. Overall, combination of bedaquiline (400 mg qd for 2 weeks, followed by 200 mg biw for 46 weeks) with clarithromycin seems a suitable regimen to be explored for efficacy and safety against PNTM. This article is protected by copyright. All rights reserved.