Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Towngrid.7836.a, Cape Town, South Africa.
Antimicrob Agents Chemother. 2022 Mar 15;66(3):e0174921. doi: 10.1128/AAC.01749-21. Epub 2022 Jan 10.
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 () deviation before interruption and after reloading were assessed to evaluate the efficacy and safety, respectively, of the reloading strategies. Bedaquiline weekly AUC and M2 deviation 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 M2 . This study presents easy-to-implement reloading strategies for restarting a patient on bedaquiline treatment after an interruption.
耐多药结核病患者经常中断治疗。贝达喹啉的终末半衰期较长；因此，中断治疗后不给予负荷剂量重新开始治疗可能会增加治疗效果不佳和耐药发展的风险。我们旨在确定贝达喹啉中断后重新开始治疗时最合适的负荷剂量策略。进行了基于模型的模拟研究。为不同持续时间和治疗中断起始点的 5000 名虚拟患者模拟了贝达喹啉及其代谢物 M2（与 QT 延长相关）的药代动力学曲线。评估中断前和重新加载后的每周贝达喹啉浓度-时间曲线下面积（AUC）和 M2 最大浓度（）偏差，分别评估疗效和安全性。贝达喹啉每周 AUC 和 M2 偏差主要受中断持续时间的驱动，仅受中断起始点的轻微影响。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 年和超过 1 年的中断，分别建议重新加载 3 天、1 周和 2 周。与不重新加载相比，这种重新加载策略导致平均贝达喹啉 AUC 偏差分别为 1.88%至 5.98%和 -16.4%至 -59.8%，中断 2 周和 1 年，而 M2 无增加。本研究提出了一种简单易行的重新加载策略，用于在中断后重新开始贝达喹啉治疗。
