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Pharmacokinetics and Safety of Clofazimine in Children With Rifampicin-Resistant Tuberculosis
Jennifer A Hughes1, Belén P Solans2,3, Anthony J Garcia-Prats1,4
1Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
Insights
Clofazimine treatment for multidrug-resistant tuberculosis in children resulted in higher drug exposures than in adults. This increased exposure may pose risks, including QT interval prolongation, especially when combined with other medications.
Area of Science:
- Pharmacology
- Pediatric Infectious Diseases
- Tuberculosis Research
Background:
- Multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) requires effective treatment options for children.
- Clofazimine is a key drug in MDR/RR-TB regimens, but its use in pediatric populations requires careful pharmacokinetic and safety evaluation.
- Understanding clofazimine exposure in children is crucial for optimizing treatment and minimizing adverse events.
Purpose of the Study:
- To evaluate the pharmacokinetics of clofazimine in children treated for MDR/RR-TB.
- To assess the safety profile of clofazimine in this pediatric cohort.
- To compare pediatric clofazimine exposure with established adult targets.
Main Methods:
- A pharmacokinetic study involving children under 18 years old treated with weight-based clofazimine doses.
- Sparse and semi-intensive blood sampling at baseline, week 2, and week 16 to determine clofazimine weekly area under the concentration-time curve (wAUC).
- Safety monitoring included QT interval measurements and laboratory assessments, with comparisons to adult wAUC targets.
Main Results:
- Twenty children (median age 6.0 years) were included in the study.
- Median clofazimine wAUC was significantly higher (over 25%) in children compared to the target adult wAUC for MDR/RR-TB.
- No serious cardiac events occurred, but a positive association between clofazimine concentration and QT interval prolongation was observed; one case of elevated liver enzymes led to temporary drug withdrawal.
Conclusions:
- Pediatric weight-based dosing of clofazimine leads to substantially higher drug exposures than in adults on standard doses.
- The increased exposure and associated QT interval prolongation risk in children warrant caution, particularly when co-administered with other QT-prolonging agents.
- Further research is needed to establish optimal and safe clofazimine dosing strategies for pediatric MDR/RR-TB treatment.
Background:
We described the pharmacokinetics and safety of clofazimine in children treated for multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB).
Methods:
Children aged <18 years were eligible. Clofazimine was administered by weight-based dosing. Sparse and semi-intensive pharmacokinetic sampling was completed at baseline and weeks 2 and 16. Clofazimine weekly area under the concentration time-curve (wAUC) was compared with the target wAUC (60.87 mg × h/L and 111.79 mg × h/L) in adults receiving clofazimine (100 mg) daily for MDR/RR-TB and leprosy, respectively. Safety monitoring included measurement of QT interval prolongation and laboratory assessment.
Results:
Twenty children were included: median age was 6.0 years (IQR, 1.6-14.4); 6 (30%) were male. Median clofazimine wAUC was 162.94 (IQR, 130.06-263.95), >25% higher than the target adult wAUC in adults with MDR/RR-TB (111.79; IQR, 81.9-151.9). No serious or grade ≥3 cardiac events occurred. There was a QT interval increase of 0.02 milliseconds for every 1-µg/L increase in clofazimine concentration. One severe adverse event (elevated alanine transferase) led to temporary withdrawal of clofazimine.
Conclusions:
The clofazimine doses used achieved substantially higher exposures in children than adults receiving standard clofazimine doses. The association of higher clofazimine exposures and QT interval prolongation may pose unnecessary risk to children, particularly in combination with other QT-prolonging drugs.
Clinical Trials Registration:
South African National Clinical Trials Register (https://sanctr.samrc.ac.za/; DOH-27-0620-6415).
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