Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, Cape Town 8000, South Africa.
Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, 2870 University Avenue, Suite 200, Madison, WI 53705, USA.
J Antimicrob Chemother. 2021 Nov 12;76(12):3237-3246. doi: 10.1093/jac/dkab336.
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.
To characterize the pharmacokinetics and safety of high rifampicin doses in children with drug-susceptible TB.
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].
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.
High rifampicin doses in children achieved target exposures and the doses evaluated were safe over 2 weeks.
成人 40mg/kg 的利福平剂量安全且耐受良好，可能缩短抗结核治疗时间并改善治疗结局，但尚未在儿童中进行评估。
描述药物敏感结核病儿童中高剂量利福平的药代动力学和安全性。
Opti-Rif 试验纳入了 20 名 0-12 岁的儿童剂量队列，每个后续队列都进行剂量递增，直到达到目标暴露或出现安全性问题。第 1 个队列以 15mg/kg 的利福平剂量治疗 14 天，第 15 天单次给予较高剂量（35mg/kg）。采用群体模型分析第 14 天和第 15 天的药代动力学数据，并审查安全性数据。从更新后的模型中模拟下一个队列（第 1-14 天和第 15 天）的递增利福平剂量，直至达到预期目标暴露的剂量[235mg/L·h，成人接受 35mg/kg 剂量时 0 至 24 小时的浓度时间曲线下面积（AUC0-24）几何平均值]。
共有 62 名儿童入组了 3 个队列。总体中位年龄为 2.1 岁（范围=0.4-11.7）。第 2 个队列的评估剂量约为 35mg/kg（第 1-14 天）和 50mg/kg（第 15 天），第 3 个队列的评估剂量约为 60mg/kg（第 1-14 天）和 75mg/kg（第 15 天）。约一半的参与者发生与研究利福平相关的不良事件；均无 3 级或更高级别的不良事件。儿童需要 65-70mg/kg 的利福平剂量才能达到目标暴露。
儿童高剂量利福平达到了目标暴露，2 周内评估剂量是安全的。
