An Interactive Pharmacokinetic-Pharmacodynamic Framework to Evaluate Bedaquiline Dose Modifications in Adults With Tuberculosis

Abstract

Bedaquiline is approved for use in a thrice-weekly dosing schedule; simpler once-daily dosing strategies could enable fixed-dose combinations and improve patient adherence. We developed an interactive R Shiny simulation tool to enable the evaluation of different bedaquiline dosing schedules within an integrated dose-pharmacokinetic-efficacy-safety-outcome framework. Four models describing bedaquiline and its metabolite M2 concentrations, time-to-positivity sputum culture results, QTc intervals, and long-term outcomes were incorporated in the framework. A virtual population representative of tuberculosis patients was generated for simulation. Two case studies were investigated: (1) alternative bedaquiline dosing regimens and (2) bedaquiline treatment interruption and reinitiation. The ZeNix once-daily dosing (200 mg once daily for 8 weeks, followed by 100 mg once daily for 16 weeks) yielded 50% lower median bedaquiline and M2 weekly average concentrations compared to the registered (approved) and standard-loading once-daily dosing (400 mg once daily for 2 weeks, followed by 100 mg once daily for 22 weeks) at 2 weeks. The exposure difference was predicted to lead to 11% fewer patients with negative cultures at 2 weeks and 5.8% fewer patients having sputum culture conversions at 8 weeks under the ZeNix dosing. The QTcF intervals were predicted from 376 to 442 ms (5th to 95th percentile of the population) for the three evaluated strategies. We also demonstrated that the Shiny application could guide decisions on the timing and doses for reloading bedaquiline after treatment interruption. The developed Shiny platform supports future exploration of bedaquiline treatment under different scenarios, for example, potential drug–drug interactions and clinical trial simulations.