Model-Informed Once-Daily Dosing Strategy for Bedaquiline and Delamanid in Children, Adolescents and Adults with Tuberculosis.

Abstract

The complexity of the currently registered dosing schedules for bedaquiline and delamanid is a barrier to uptake in drug-resistant tuberculosis treatment across all ages. A simpler once-daily dosing schedule is critical to ensure patient-friendly regimens with good adherence. We assessed expected drug exposures with proposed once-daily doses for adults and compared novel model-informed once-daily dosing strategies for children with current World Health Organization (WHO) recommended dosing. A reference individual and virtual pediatric population were generated to simulate exposures in adults and children, respectively. Published population models characterizing the exposures of bedaquiline and its metabolite M2, delamanid, and its metabolite DM-6705 were utilized. During simulation, child growth during treatment along with several CYP3A4 ontogeny profiles was accounted for. Exposures in children were compared with simulated adult targets to assess the expected treatment efficacy and safety. In adults, the proposed bedaquiline once-daily dosing (400 mg daily for 2 weeks followed by 100 mg daily for 22 weeks) yielded 14% higher exposures of bedaquiline and M2 compared to the labeled dosing scheme at 24 weeks; for delamanid and DM-6705, the suggested 300 mg daily dose provided 13% lower exposures at steady state. For children, the cumulative proportions of exposures of both drugs showed < 5% difference between WHO-recommended and proposed once-daily dosing. This study demonstrated the use of model-informed approaches to propose rational and simpler regimens for bedaquiline and delamanid in adults and children. The new once-daily dosing strategies will be tested in the PARADIGM4TB and IMPAACT 2020 trials in adults and children, respectively.