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

Abstract 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).