Pharmacodynamics and the Bactericidal Activity of Bedaquiline in Pulmonary Tuberculosis

Bedaquiline is a diarylquinoline antimycobacterial drug and a key component of several regimens in clinical development for 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 two days followed by once daily 100 mg, 200 mg, 300 mg, or 400 mg. The modeling results included expected values (mean±SD) for a maximum drug kill rate constant equal to 0.23±0.03 log 10 CFU/mL sputum/day, a half-maximum effect 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 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 log 10 CFU/mL/day, or 10 h/day assessed by liquid culture time to positivity (TTP). Additional simulations illustrated efficacy outcomes during eight weeks of treatment with the recommended and alternative dosages. The results demonstrate a general mathematical and statistical approach to analysis of EBA studies with broad application to TB regimen development.