Journal
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
Volume 76, Issue 12, Pages 3237-3246Publisher
OXFORD UNIV PRESS
DOI: 10.1093/jac/dkab336
Keywords
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Funding
- TB Alliance through the Unitaid
- South African National Research Foundation SARChi Chair in Paediatric Tuberculosis
- Adult Clinical Trial Group (ACTG) via the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health [UM1 AI068634, UM1 AI068636, UM1 AI106701]
- Infant Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT)
- National Institute of Allergy and Infectious Diseases [U01 AI068632]
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
- National Institute of Mental Health [AI068632]
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The study evaluated the pharmacokinetics and safety of high rifampicin doses in 20 children aged 0-12 years, finding that a dose of 65-70 mg/kg of rifampicin was needed to achieve the target exposure in children.
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 24h (AUC(0-24)) among adults receiving a 35mg/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 similar to 35 mg/kg (days 1-14) and similar to 50 mg/kg (day 15) for cohort 2 and similar to 60 mg/kg (days 1-14) and similar to 75mg/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.
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