贝达喹啉在耐利福平结核病的 HIV 阳性和阴性大龄儿童和青少年中的药代动力学和安全性。
Pharmacokinetics and Safety of Bedaquiline in Human Immunodeficiency Virus (HIV)-Positive and Negative Older Children and Adolescents With Rifampicin-Resistant Tuberculosis.
机构信息
Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco Schools of Pharmacy and Medicine, San Francisco, California, USA.
出版信息
Clin Infect Dis. 2022 Nov 14;75(10):1772-1780. doi: 10.1093/cid/ciac252.
BACKGROUND
Pharmacokinetic data for bedaquiline in children are limited. We described the pharmacokinetics and safety of bedaquiline in South African children and adolescents receiving treatment for multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) in routine care.
METHODS
In this observational cohort study, children aged 6-17 years receiving bedaquiline at recommended doses as part of MDR/RR-TB treatment underwent semi-intensive pharmacokinetic sampling. Bedaquiline and the M2 metabolite plasma concentrations were quantified, and nonlinear mixed-effects modeling performed. Pediatric data were described using a pre-established model of bedaquiline pharmacokinetics in adults. The exposure reference was 187 µg ⋅ h/mL, the median weekly area under the curve (AUC) of adults at week 24 of treatment with bedaquiline. Safety was assessed through monthly clinical, blood and electrocardiogram monitoring, and treatment outcomes described.
RESULTS
Fifteen children (3 human immunodeficiency virus [HIV]-positive) with median age 13.3 years (range 6.5-16.3) were included. A bedaquiline pharmacokinetic model was adapted to be allometrically scaled in clearance and volume, centered in the median child population weight. Bedaquiline bioavailability was 57% of that in adults. Overall bedaquiline exposures were below target, and AUC reference attainment was achieved in only 3 (20%) children. Ten children experienced 27 adverse events at least possibly related to bedaquiline; no adverse events led to bedaquiline withdrawal. Two adverse events (arthritis and arthralgia) were considered severe, and 2 children had mild QT interval corrected for heart rate using Fridericia's formula (QT) prolongation.
CONCLUSIONS
The evaluated doses of bedaquiline in children ≥ 6 years of age were safe but achieved slightly lower plasma concentrations compared to adults receiving the recommended dose, possibly due to delayed food intake relative to bedaquiline administration.
背景
目前关于贝达喹啉在儿童中的药代动力学数据有限。本研究旨在描述贝达喹啉在南非儿童和青少年中的药代动力学特征和安全性，这些儿童和青少年正在接受常规护理下的耐多药/利福平耐药结核病（MDR/RR-TB）治疗。
方法
在这项观察性队列研究中，6-17 岁的儿童正在接受 MDR/RR-TB 治疗，接受贝达喹啉推荐剂量治疗，并进行半强化药代动力学采样。检测贝达喹啉和 M2 代谢物的血药浓度，采用非线性混合效应模型进行分析。采用成人贝达喹啉药代动力学的既定模型来描述儿科数据。参考暴露量为 187µg·h/mL，即成人接受贝达喹啉治疗 24 周时的每周 AUC 中位数。通过每月临床、血液和心电图监测来评估安全性，并描述治疗结局。
结果
共纳入 15 例儿童（3 例人类免疫缺陷病毒[HIV]阳性），中位年龄为 13.3 岁（范围 6.5-16.3）。采用房室模型法对贝达喹啉药代动力学模型进行了体表面积校正，以儿童人群的体重中位数为中心。贝达喹啉的生物利用度为成人的 57%。总体贝达喹啉暴露量低于目标值，仅 3 例（20%）儿童达到 AUC 参考值。10 例儿童至少出现过 1 次与贝达喹啉至少可能相关的不良事件 27 次；没有因不良事件而停用贝达喹啉。2 例不良事件（关节炎和关节痛）被认为是严重的，2 例儿童出现轻度 Fridericia 公式校正的 QT 间期延长（QT）。
结论
在本研究中，评估剂量的贝达喹啉在 6 岁以上儿童中是安全的，但与接受推荐剂量的成人相比，其血浆浓度略低，这可能是由于与成人相比，儿童进食时间相对延迟。
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