Peer-reviewed article
Pharmacokinetics and cardiac safety of clofazimine in children with rifampicin-resistant tuberculosis
Ali Mohamed Ali, Belén P. Solans, Anneke Catharina Hesseling, Jana L. Winckler, Hendrik Simon Schaaf et al. ·
Summary
Written by AI, not yet AICS's view · claude-haiku-4-5-20251001This study examined how the drug clofazimine works in children with drug-resistant tuberculosis and whether it causes heart problems. Researchers measured drug levels and heart electrical activity in 54 South African children aged under 18 years receiving clofazimine treatment. The drug reached higher levels in children compared to adults, but did not cause severe heart rhythm problems, though there was a measurable relationship between drug concentration and heart electrical changes.
Key points
- Clofazimine exposure in children using off-label dosing was higher than in adults (79.1 mg.h/L versus adult target of 60.9 mg.h/L)
- Children living with HIV had four times higher clearance of clofazimine compared to HIV-negative children
- No child had QTcF ≥500 ms, indicating severe heart rhythm prolongation was not observed
- A linear dose-response relationship was found between clofazimine concentration and QTcF interval prolongation
- Current dosing strategies for children are off-label with limited evidence to guide optimal dosing
Limitations
This was an observational study without a control group, so causality cannot be definitively established. The findings are from South Africa and may not generalise to other settings, and only 54 children were included with only 5 living with HIV, limiting the power to detect effects in specific subgroups.
Abstract
Clofazimine is recommended for the treatment of rifampicin-resistant tuberculosis (RR-TB), but there is currently no verified dosing guideline for its use in children. There is only limited safety and no pharmacokinetic (PK) data available for children. We aimed to characterize clofazimine PK and its relationship with QT-interval prolongation in children. An observational cohort study of South African children <18 years old routinely treated for RR-TB with a clofazimine-containing regimen was analyzed. Clofazimine 100 mg gelatin capsules were given orally once daily (≥20 kg body weight), every second day (10 to <20 kg), or thrice weekly (<10 kg). PK sampling and electrocardiograms were completed pre-dose and at 1, 4, and 10 hours post-dose, and the population PK and Fridericia-corrected QT (QTcF) interval prolongation were characterized. Fifty-four children contributed both PK and QTcF data, with a median age (2.5th-97.5th centiles) of 3.3 (0.5-15.6) years; five children were living with HIV. Weekly area under the time-concentration curve at steady state was 79.1 (15.0-271) mg.h/L compared to an adult target of 60.9 (56.0-66.6) mg.h/L. Children living with HIV had four times higher clearance compared to those without. No child had a QTcF ≥500 ms. A linear concentration-QTcF relationship was found, with a drug effect of 0.05 (0.027, 0.075) ms/µg/L. In some of the first PK data in children, we found clofazimine exposure using an off-label dosing strategy was higher in children versus adults. Clofazimine concentrations were associated with an increase in QTcF, but severe prolongation was not observed. More data are required to inform dosing strategies in children.
Findings the Hub has extracted
Each claim below is labelled by its type of design and links back to this report.
- Intervention
- Clofazimine treatment with weight-based dosing: 100 mg once daily (≥20 kg), every second day (10 to <20 kg), or thrice weekly (<10 kg)
- Population
- 54 South African children aged <18 years (median 3.3 years, range 0.5-15.6 years) with rifampicin-resistant tuberculosis, including 5 living with HIV
Key finding
Weekly area under the curve at steady state was 79.1 mg.h/L in children versus adult target of 60.9 mg.h/L