Pharmacokinetics and safety of rifapentine in children: dosing for latent tuberculosis infection.

Abstract

Objectives: To assess the safety of 4-week daily rifapentine-isoniazid regimen in latent tuberculosis for Chinese children, and to provide paediatric-specific evidence for extrapolating adult dosing strategies to children.

Methods: An open-label, prospective, single-arm clinical trial was conducted among eligible patients (aged <10 years old). Rifapentine concentrations and laboratory safety biomarker (total bilirubin) were analysed and used for population pharmacokinetic-toxicity model development. Simulations were performed to compare efficacy and safety of weight-based and flat-dosing strategy.

Results: Once-daily rifapentine treatment was well tolerated: 310 samples (rifapentine n = 139; total bilirubin n = 171) from 36 children (age range 0.89-10 years) were captured well by a joint one-compartment pharmacokinetic with time-varying clearance and an indirect response model. The model adequately described rifapentine autoinduction, reaching a plateau after 21 days and increasing clearance by 70.4%. Simulation suggested that weight-based dosing may cause underexposure in children under 14.5 kg. A flat-dosing strategy could ensure plasma levels within the therapeutic windows. Rifapentine's impact on total bilirubin was within a 2-fold range, and the effect subsided within 5 days after discontinuation.

Conclusions: Our study suggested that a flat-dosing strategy of rifapentine was potentially safe and effective for latent tuberculosis infection treatment in Chinese children aged 1 to 10 years old.