Pharmacokinetics and Safety of Bedaquiline in HIV-Positive and Negative Older Children and Adolescents with Rifampicin-Resistant Tuberculosis

Abstract Background Pharmacokinetic data for bedaquiline in children are limited. We described the pharmacokinetics and safety of bedaquiline in South African children and adolescents receiving treatment for multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) in routine care. Methods In this observational cohort study, children aged 6-17 years receiving bedaquiline at recommended doses as part of MDR/RR-TB treatment underwent semi-intensive pharmacokinetic sampling. Bedaquiline and the M2 metabolite plasma concentrations were quantified, and nonlinear mixed-effects modelling performed. Paediatric data were described using a pre-established model of bedaquiline pharmacokinetics in adults. The exposure reference was 187 µg.h/mL, the median weekly area under the curve (AUC) of adults at week 24 of treatment with bedaquiline. Safety was assessed through monthly clinical, blood and electrocardiogram monitoring, and treatment outcomes described. Results Fifteen children (three HIV-positive) with median age 13.3 years (range 6.5-16.3) were included. A bedaquiline pharmacokinetic model was adapted to be allometrically scaled in clearance and volume, centred in the median child population weight. Bedaquiline bioavailability was 57% of that in adults. Overall bedaquiline exposures were below target, AUC reference attainment was achieved in only three (20%) children. Ten children experienced 27 adverse events at least possibly related to bedaquiline; no adverse events led to bedaquiline withdrawal. Two adverse events (arthritis and arthralgia) were considered severe, and two children had mild QT prolongation. Conclusions The evaluated doses of bedaquiline in children ≥6 years of age were safe but achieved slightly lower plasma concentrations compared to adults receiving the recommended dose, possibly due to delayed food intake relative to bedaquiline administration.