Pharmacokinetics and safety of high-dose rifampicin in children with TB: the Opti-Rif trial

Abstract Background Rifampicin doses of 40 mg/kg in adults are safe and well tolerated, may shorten anti-TB treatment and improve outcomes, but have not been evaluated in children. Objectives To characterize the pharmacokinetics and safety of high rifampicin doses in children with drug-susceptible TB. Patients and methods The Opti-Rif trial enrolled dosing cohorts of 20 children aged 0–12 years, with incremental dose escalation with each subsequent cohort, until achievement of target exposures or safety concerns. Cohort 1 opened with a rifampicin dose of 15 mg/kg for 14 days, with a single higher dose (35 mg/kg) on day 15. Pharmacokinetic data from days 14 and 15 were analysed using population modelling and safety data reviewed. Incrementally increased rifampicin doses for the next cohort (days 1–14 and day 15) were simulated from the updated model, up to the dose expected to achieve the target exposure [235 mg/L·h, the geometric mean area under the concentration–time curve from 0 to 24 h (AUC0–24) among adults receiving a 35 mg/kg dose]. Results Sixty-two children were enrolled in three cohorts. The median age overall was 2.1 years (range = 0.4–11.7). Evaluated doses were ∼35 mg/kg (days 1–14) and ∼50 mg/kg (day 15) for cohort 2 and ∼60 mg/kg (days 1–14) and ∼75 mg/kg (day 15) for cohort 3. Approximately half of participants had an adverse event related to study rifampicin; none was grade 3 or higher. A 65–70 mg/kg rifampicin dose was needed in children to reach the target exposure. Conclusions High rifampicin doses in children achieved target exposures and the doses evaluated were safe over 2 weeks.