Optimized Loading Dose Strategies for Bedaquiline When Restarting Interrupted Drug-Resistant Tuberculosis Treatment.
Optimized Loading Dose Strategies for Bedaquiline When Restarting Interrupted Drug-Resistant Tuberculosis Treatment.
复制标题
重新开始中断的耐药结核病治疗时贝达喹啉的优化负荷剂量策略。
DOI：
10.1128/aac.01749-21
复制
发表时间：
2022
影响因子：
4.9
通讯作者：
Svensson,ElinM
中科院分区：
文献类型：
--
作者：
Koele,SimonE;vanBeek,StijnW;Maartens,Gary;Brust,JamesCM;Svensson,ElinM
治疗中断在耐药结核病患者中很常见。贝达喹啉具有较长的终末半衰期;因此，在中断后重新开始而不使用负荷剂量可能会增加次优治疗结局和耐药性发展的风险。我们的目的是确定贝达喹啉中断后重新开始的最合适的负荷剂量策略。进行了基于模型的模拟研究。模拟了5，000例虚拟患者在不同治疗中断持续时间和起始点的贝达喹啉及其代谢产物M2（与QT间期延长相关）的药代动力学特征。每周一次评估中断前和重新加载后的贝达喹啉浓度-时间曲线下面积（AUC）和M2最大浓度（Cmax）偏差，以分别评价重新加载策略的疗效和安全性。贝达喹啉每周AUC和M2Cmax偏差主要由中断持续时间驱动，仅少量由中断起始点驱动。对于持续时间短于2周的中断，不需要新的负荷剂量。对于持续时间在2周至1个月、1个月至1年以及1年以上的中断，建议分别重新加载3天、1周和2周。这种重新加载策略导致贝达喹啉AUC的平均偏差为1.88%-5.98%，而在未重新加载的情况下，分别中断2周和1年，平均偏差为-16.4%-59.8%，且未增加M2Cmax。本研究提出了易于实施的重新加载策略，用于在中断后重新开始贝达喹啉治疗的患者。
Interruption of treatment is common in drug-resistant tuberculosis patients. Bedaquiline has a long terminal half-life; therefore, restarting after an interruption without a loading dose could increase the risk of suboptimal treatment outcome and resistance development. We aimed to identify the most suitable loading dose strategies for bedaquiline restart after an interruption. A model-based simulation study was performed. Pharmacokinetic profiles of bedaquiline and its metabolite M2 (associated with QT prolongation) were simulated for 5,000 virtual patients for different durations and starting points of treatment interruption. Weekly bedaquiline area under the concentration-time curve (AUC) and M2 maximum concentration (Cmax) deviation before interruption and after reloading were assessed to evaluate the efficacy and safety, respectively, of the reloading strategies. Bedaquiline weekly AUC and M2Cmaxdeviation were mainly driven by the duration of interruption and only marginally by the starting point of interruption. For interruptions with a duration shorter than 2 weeks, no new loading dose is needed. For interruptions with durations between 2 weeks and 1 month, 1 month and 1 year, and longer than 1 year, reloading periods of 3 days, 1 week, and 2 weeks, respectively, are recommended. This reloading strategy results in an average bedaquiline AUC deviation of 1.88% to 5.98% compared with −16.4% to −59.8% without reloading for interruptions of 2 weeks and 1 year, respectively, without increasing M2Cmax. This study presents easy-to-implement reloading strategies for restarting a patient on bedaquiline treatment after an interruption.