Pharmacodynamics and Bactericidal Activity of Bedaquiline in Pulmonary Tuberculosis.

Abstract

Bedaquiline is a diarylquinoline antimycobacterial drug and a key component of several regimens in clinical development for the treatment of tuberculosis (TB) but with ongoing phase 3 trials that include assessment of simplified dosing. A pharmacokinetic-pharmacodynamic model of bedaquiline Mycobacterium tuberculosis-killing kinetics in adults with pulmonary TB was developed to inform dose selection of bedaquiline-containing regimens. The model parameters were estimated with data from the 14-day early bactericidal activity (EBA) study TMC207-CL001 conducted in Cape Town, South Africa. The study included 60 adult males and females with drug-susceptible pulmonary TB, who were administered bedaquiline with loading doses on the first 2 days followed by once-daily 100 mg, 200 mg, 300 mg, or 400 mg. The modeling results included expected values (means ± standard deviations [SDs]) for a maximum drug kill rate constant equal to 0.23 ± 0.03 log10 CFU/mL sputum/day, a half-maximum effective plasma concentration equal to 1.6 ± 0.3 mg/L, and an average time to onset of activity equal to 40 ± 7 h. Model simulations showed that once-daily 200 mg, 300 mg, and 400 mg (without loading doses) attained 40%, 50%, and 60%, respectively, of an expected maximum 14-day EBA equal to 0.18 log10 CFU/mL/day, or 10 h/day assessed by liquid culture time to positivity (TTP). Additional simulations illustrated efficacy outcomes during 8 weeks of treatment with the recommended and alternative dosages. The results demonstrate a general mathematical and statistical approach to the analysis of EBA studies with broad application to TB regimen development.