Optimized loading dose strategies for bedaquiline when restarting interrupted drug-resistant tuberculosis treatment

Interruption of treatment is common in drug-resistant tuberculosis patients. Bedaquiline has a long terminal half-life therefore, restarting after an interruption without a loading dose could increase the risk of suboptimal treatment outcome and resistance development. We aimed to identify the most suitable loading dose strategies for bedaquiline restart after an interruption. A model-based simulation study was performed. Pharmacokinetic profiles of bedaquiline and its metabolite M2 (associated with QT-prolongation) were simulated for 5000 virtual patients for different durations and starting points of treatment interruption. Weekly bedaquiline area under the concentration-time curve (AUC) and M2 maximum concentration (Cmax) deviation before interruption and after reloading were assessed to evaluate the efficacy and safety respectively of the reloading strategies. Bedaquiline weekly AUC and M2 Cmax deviation were mainly driven by the duration of interruption and only marginally by the starting point of interruption. For interruptions with a duration shorter than two weeks, no new loading dose is needed. For interruptions with durations between two weeks and one month, one month and one year, and longer than one year, reloading periods of three days, one week, and two weeks, respectively, are recommended. This reloading strategy results in an average bedaquiline AUC deviation of 1.88% to 5.98% compared with -16.4% to -59.8% without reloading for interruptions of two weeks and one year respectively, without increasing M2 Cmax. This study presents easy-to-implement reloading strategies for restarting a patient on bedaquiline treatment after an interruption.