Background Each year 25 000–32 000 children develop rifampicin- or multidrug-resistant tuberculosis (RR/MDR-TB), and many more require preventive treatment. Levofloxacin is a key component of RR/MDR-TB treatment and prevention, but the existing pharmacokinetic data in children have not yet been comprehensively summarized. We aimed to characterize levofloxacin pharmacokinetics through an individual patient data meta-analysis of available studies and to determine optimal dosing in children. Methods Levofloxacin concentration and demographic data were pooled from 5 studies and analyzed using nonlinear mixed effects modeling. Simulations were performed using current World Health Organization (WHO)–recommended and model-informed optimized doses. Optimal levofloxacin doses were identified to target median adult area under the time-concentration curve (AUC)24 of 101 mg·h/L given current standard adult doses. Results Data from 242 children (2.8 years [0.2–16.8] was used). Apparent clearance was 3.16 L/h for a 13-kg child. Age affected clearance, reaching 50% maturation at birth and 90% maturation at 8 months. Nondispersible tablets had 29% lower apparent oral bioavailability compared to dispersible tablets. Median exposures at current WHO-recommended doses were below the AUC target for children weighing <24 kg and under <10 years, resulting in approximately half of the exposure in adults. Model-informed doses of 16–33 mg/kg for dispersible tablets or 16–50 mg/kg for nondispersible tablets were required to meet the AUC target without significantly exceeding the median adult Cmax. Conclusions Revised weight-band dosing guidelines with doses of >20 mg/kg are required to ensure adequate exposure. Further studies are needed to determine safety and tolerability of these higher doses.

中文翻译：

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儿童耐药结核病左氧氟沙星的药代动力学和最佳剂量：个体患者数据荟萃分析

背景 每年有 25 000-32 000 名儿童患上利福平或多药耐药结核病 (RR/MDR-TB)，还有更多儿童需要预防性治疗。左氧氟沙星是RR/MDR-TB治疗和预防的关键成分，但现有的儿童药代动力学数据尚未全面总结。我们的目的是通过对现有研究的个体患者数据荟萃分析来表征左氧氟沙星的药代动力学，并确定儿童的最佳剂量。方法 汇集 5 项研究的左氧氟沙星浓度和人口统计数据，并使用非线性混合效应模型进行分析。使用当前世界卫生组织 (WHO) 推荐和基于模型的优化剂量进行模拟。确定了最佳左氧氟沙星剂量，以在当前标准成人剂量下，时间-浓度曲线 (AUC)24 为 101 mg·h/L 时成人中位面积为目标。结果 数据来自 242 名儿童（使用 2.8 岁 [0.2–16.8]）。对于 13 公斤重的儿童，表观清除率为 3.16 升/小时。年龄影响清除率，出生时达到 50% 成熟，8 个月时达到 90% 成熟。与分散片相比，非分散片的表观口服生物利用度低 29%。当前世界卫生组织推荐剂量下的中位暴露量低于体重<24公斤和<10岁儿童的AUC目标，导致成人暴露量的大约一半。分散片的模型剂量为 16-33 mg/kg，非分散片的模型剂量为 16-50 mg/kg，才能满足 AUC 目标，且不显着超过成人 Cmax 中位数。结论 需要修订剂量>20mg/kg的体重带剂量指南以确保足够的暴露。需要进一步的研究来确定这些较高剂量的安全性和耐受性。