Population pharmacokinetics and dosing of dispersible moxifloxacin formulation in children with rifampicin-resistant tuberculosis

IF 3.1 3区医学 Q2 PHARMACOLOGY & PHARMACY

British journal of clinical pharmacology Pub Date : 2025-05-29 DOI:10.1111/bcp.70005

Megan Palmer, Yuanxi Zou, Anneke C. Hesseling, Louvina van der Laan, Ingrid Courtney, Aarti A. Kinikar, Naresh Sonkawade, Mandar Paradkar, Vandana Kulkarni, Dessa Jean O. Casalme, Melchor V. G. Frias, Heather Draper, Lubbe Wiesner, Mats O. Karlsson, Paolo Denti, Elin M. Svensson, Anthony J. Garcia-Prats

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引用次数: 0

Abstract

Aims

Moxifloxacin is a priority drug for treating rifampicin-resistant tuberculosis (RR-TB). We assessed the pharmacokinetics of a child-friendly, dispersible 100 mg tablet moxifloxacin formulation (dispersed in water) compared to the standard 400 mg non-dispersible formulation (crushed and suspended in water) in children and evaluated current dosing recommendations.

Methods

The CATALYST trial investigated the pharmacokinetics of moxifloxacin in children with RR-TB. Children were enrolled in South Africa, India and the Philippines. Intensive pharmacokinetic sampling was undertaken while children were taking the standard non-dispersible 400 mg moxifloxacin tablet formulation and repeated after switching to the novel dispersible formulation. Pharmacokinetic data were analysed using population pharmacokinetic modelling. Simulations were performed to evaluate moxifloxacin exposures in children compared to consensus adult reference exposures using current World Health Organization (WHO)-recommended doses and more recent model-based doses.

Results

Thirty-six children were enrolled [median age 4.8 (range 0.4–15) years and weight 15.6 (range 6.9–42.1) kg]. A two-compartment disposition model with first-order elimination and delayed absorption was developed. The bioavailability of dispersible versus standard formulations fulfilled standard bioequivalence criterion (ratio 1.05 with 90% confidence interval 0.95–1.15). Simulations showed WHO-recommended doses achieved exposures similar to those in adults in children >10 kg, while children <10 kg may require 33%–56% higher doses to reach adult reference exposures.

Conclusions

Dosing recommendations for children can be the same for the dispersible paediatric and standard non-dispersible adult moxifloxacin formulation. The current WHO dosing recommendation risks underdosing moxifloxacin in children <10 kg. We propose optimized moxifloxacin doses for both formulations.

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分散莫西沙星制剂在耐利福平结核儿童中的人群药代动力学和剂量

目的莫西沙星是治疗耐利福平结核的首选药物。我们评估了儿童友好的100毫克分散莫西沙星片剂（分散在水中）与标准400毫克非分散制剂（粉碎并悬浮在水中）在儿童中的药代动力学，并评估了目前的剂量建议。方法采用CATALYST试验研究莫西沙星在儿童RR-TB中的药动学。儿童在南非、印度和菲律宾注册。在儿童服用标准的400 mg莫西沙星非分散制剂时，进行了密集的药代动力学采样，并在切换到新的分散制剂后重复采样。采用群体药代动力学模型分析药代动力学数据。采用世界卫生组织（WHO）当前推荐剂量和最近基于模型的剂量，模拟评估儿童莫西沙星暴露与成人参考暴露的比较。结果纳入36名儿童[中位年龄4.8（0.4-15）岁，体重15.6 (6.9-42.1)kg]。建立了一阶消除和延迟吸收的双室配置模型。分散剂与标准制剂的生物利用度符合标准生物等效性标准（比值为1.05,90%置信区间为0.95 ~ 1.15）。模拟结果显示，世卫组织推荐剂量达到的暴露量与儿童（10kg）的成人相似，而儿童（10kg）可能需要高出33%-56%的剂量才能达到成人参考暴露量。结论莫西沙星儿童分散剂型和成人非分散剂型的推荐剂量相同。世卫组织目前的剂量建议存在儿童莫西沙星剂量不足10公斤的风险。我们提出了两种配方的最佳莫西沙星剂量。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

British journal of clinical pharmacology 医学-药学

CiteScore

6.30

自引率

8.80%

发文量

419

审稿时长

1 months

期刊介绍： Published on behalf of the British Pharmacological Society, the British Journal of Clinical Pharmacology features papers and reports on all aspects of drug action in humans: review articles, mini review articles, original papers, commentaries, editorials and letters. The Journal enjoys a wide readership, bridging the gap between the medical profession, clinical research and the pharmaceutical industry. It also publishes research on new methods, new drugs and new approaches to treatment. The Journal is recognised as one of the leading publications in its field. It is online only, publishes open access research through its OnlineOpen programme and is published monthly.