Keutzer Lina, Akhondipour Salehabad Yasamin, Davies Forsman Lina, Simonsson Ulrika S H
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Division of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
CPT Pharmacometrics Syst Pharmacol. 2022 May;11(5):628-639. doi: 10.1002/psp4.12768. Epub 2022 Feb 16.
Bedaquiline (BDQ) is recommended for treatment of multidrug-resistant tuberculosis (MDR-TB) for the majority of patients. Given its long terminal half-life and safety concerns, such as QTc-prolongation, re-introducing BDQ after multiple dose interruption is not intuitive and there are currently no existing guidelines. In this simulation-based study, we investigated different loading dose strategies for BDQ re-introduction, taking safety and efficacy into account. Multiple scenarios of time and length of interruption as well as BDQ re-introduction, including no loading dose, 1- and 2-week loading doses (200 mg and 400 mg once daily), were simulated from a previously published population pharmacokinetic (PK) model describing BDQ and its main metabolite M2 PK in patients with MDR-TB. The efficacy target was defined as 95.0% of the average BDQ concentration without dose interruption during standard treatment. Because M2 is the main driver for QTc-prolongation, the safety limit was set to be below the maximal average M2 metabolite concentration in a standard treatment. Simulations suggest that dose interruptions between treatment weeks 3 and 72 (interruption length: 1 to 6 weeks) require a 2-week loading dose of 200 mg once daily in the typical patient. If treatment was interrupted for longer than 8 weeks, a 2-week loading dose (400 mg once daily) was needed to reach the proposed efficacy target, slightly exceeding the safety limit. In conclusion, we here propose a strategy for BDQ re-introduction providing guidance to clinicians for safe and efficacious BDQ dosing.
对于大多数耐多药结核病（MDR-TB）患者，推荐使用贝达喹啉（BDQ）进行治疗。鉴于其较长的终末半衰期以及诸如QTc延长等安全性问题，在多次剂量中断后重新引入BDQ并非直观可行，且目前尚无现有指南。在这项基于模拟的研究中，我们在考虑安全性和有效性的情况下，研究了BDQ重新引入的不同负荷剂量策略。从先前发表的描述MDR-TB患者中BDQ及其主要代谢物M2药代动力学（PK）的群体PK模型中，模拟了多种中断时间和长度以及BDQ重新引入的情况，包括无负荷剂量、1周和2周负荷剂量（每日一次200mg和400mg）。疗效目标定义为标准治疗期间无剂量中断时BDQ平均浓度的95.0%。由于M2是QTc延长的主要驱动因素，安全限度设定为低于标准治疗中最大平均M2代谢物浓度。模拟结果表明，在治疗第3至72周之间的剂量中断（中断长度：1至6周），典型患者需要每日一次200mg的2周负荷剂量。如果治疗中断超过8周，则需要每日一次400mg的2周负荷剂量才能达到建议的疗效目标，这会略超过安全限度。总之，我们在此提出一种BDQ重新引入的策略，为临床医生提供安全有效的BDQ给药指导。
