Pharmacokinetics and Safety of a Novel Clofazimine Formulation and Dosing Strategy in Children With Rifampicin-resistant Tuberculosis.

BACKGROUND: Clofazimine is commonly included in multidrug regimens for children with multidrug-resistant and rifampicin-resistant tuberculosis (MDR/RR-TB), but accurate pediatric dosing has been limited by 100-mg soft-gel capsules that cannot be reliably divided. We evaluated the exposure and safety of a novel 50-mg clofazimine tablet using revised once-daily weight-banded dosing informed by a previous study (Clofazimine PK1). METHODS: Children <18 years weighing <30 kg receiving MDR/RR-TB treatment, including clofazimine, were enrolled. Sparse and semi-intensive pharmacokinetic sampling was completed at baseline and at weeks 2 and 12. Model-predicted weekly steady-state area-under-the-curve (wAUCss) was compared with an adult target of 111.79 mg·h/L. Safety monitoring included clinical, laboratory, and electrocardiogram (ECG) monitoring. RESULTS: Twelve children were included (median age 2.8 years; range 0.6-8.2). Median predicted wAUCss was 106 mg·h/L (range 76.9-274), within 25% of target. Two grade 3 adverse events (drug-induced liver injury and skin hyperpigmentation) possibly related to clofazimine, but no other clofazimine-related serious adverse events, were observed, The Fridericia corrected QT (QTcF) interval typically increased with 0.042 ms per1-µg/L increase in clofazimine concentration; five QTcF prolongations (>460-480 ms) occurred in three participants. CONCLUSIONS: The revised once-daily dosing with the 50-mg clofazimine tablet achieved the predefined exposure target. Clinically important adverse events support cautious use with ECG and laboratory monitoring and further evaluation before broad adoption. CLINICAL TRIALS REGISTRATION: South African National Clinical Trials Register (https://sanctr.samrc.ac.za/; DOH-27-0620-6415).