Department of Bioengineering and Therapeutics, Schools of Pharmacy and Medicine, University of California-San Francisco, San Francisco, California, USA.
Center for Tuberculosis, University of California-San Francisco, San Francisco, California, USA.
Clin Infect Dis. 2024 Mar 20;78(3):756-764. doi: 10.1093/cid/ciae024.
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.
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.
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.
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.
每年有 25000-32000 名儿童发展为利福平或耐多药结核病（RR/MDR-TB），还有更多的儿童需要预防性治疗。左氧氟沙星是 RR/MDR-TB 治疗和预防的关键组成部分，但现有的儿童药代动力学数据尚未得到全面总结。我们旨在通过对现有研究的个体患者数据进行荟萃分析来描述左氧氟沙星的药代动力学，并确定儿童的最佳剂量。
从 5 项研究中汇集左氧氟沙星浓度和人口统计学数据，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）推荐的和基于模型优化的剂量进行模拟。确定最佳左氧氟沙星剂量，以达到当前标准成人剂量下的成人中位数 AUC24 为 101mg·h/L。
共有 242 名儿童（2.8 岁[0.2-16.8]）的数据。对于 13 公斤的儿童，表观清除率为 3.16 L/h。年龄影响清除率，出生时达到 50%成熟，8 个月时达到 90%成熟。非分散片剂的表观口服生物利用度比分散片低 29%。在当前 WHO 推荐剂量下，对于体重<24kg 和年龄<10 岁的儿童，中位暴露量低于 AUC 目标值，导致成人暴露量约为一半。分散片的 16-33mg/kg 或非分散片剂的 16-50mg/kg 的模型指导剂量可达到 AUC 目标值，而不会显著超过成人的中位 Cmax。
需要修订按体重分组的剂量指南，剂量>20mg/kg 以确保充分暴露。需要进一步研究这些更高剂量的安全性和耐受性。
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