Model-Predicted Impact of ECG Monitoring Strategies During Bedaquiline Treatment.
Model-Predicted Impact of ECG Monitoring Strategies During Bedaquiline Treatment.
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DOI：
10.1093/ofid/ofac372
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发表时间：
2022-08
影响因子：
4.2
通讯作者：
中科院分区：
文献类型：
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贝达喹啉的M2代谢产物导致QT间期延长，因此有必要对接受贝达喹啉治疗的耐药结核病患者进行心电图（ECG）监测。本研究的目的是确定M2暴露与Fridericia校正QT（QTcF）间期延长之间的关系，并探索6个月贝达喹啉治疗的适当ECG监测策略。来自PROBeX研究（一项前瞻性观察性队列研究）的数据用于描述M2暴露与QTcF之间的关系。将建立的非线性混合效应模型拟合到药代动力学和ECG数据。在虚拟患者人群中，模拟了伴随和不伴随氯法齐明的情况下的QTcF值。探索了ECG监测策略，以识别需要中断治疗（QTcF > 500 ms）的患者。纳入170例患者，提供1131个贝达喹啉/M2血浆浓度和1702个QTcF测量值; 2.1%的接受氯法齐明合并治疗的虚拟患者在治疗期间的任何时间点QTcF > 500 ms（0.7%未合并氯法齐明）。 通过每月监测，几乎所有QTcF > 500 ms的患者在第12周时均被识别;第12周后，由于随机测量误差，患者主要被错误识别为QTcF > 500 ms。 按照治疗前和第2、4、8和12周伴随氯法齐明模拟监测策略，确定了93.8%的应中断治疗的患者，26.4%的所有中断是不必要的（分别为92.1%和32.2%，无伴随氯法齐明）。我们的模拟通过权衡QTcF > 500 ms患者缺失的风险和不必要地中断贝达喹啉治疗的风险，为适当的ECG监测策略做出明智的决定。 我们建议在治疗前和开始贝达喹啉治疗后第2、4、8和12周进行ECG监测。
The M2 metabolite of bedaquiline causes QT-interval prolongation, making electrocardiogram (ECG) monitoring of patients receiving bedaquiline for drug-resistant tuberculosis necessary. The objective of this study was to determine the relationship between M2 exposure and Fridericia-corrected QT (QTcF)-interval prolongation and to explore suitable ECG monitoring strategies for 6-month bedaquiline treatment. Data from the PROBeX study, a prospective observational cohort study, were used to characterize the relationship between M2 exposure and QTcF. Established nonlinear mixed-effects models were fitted to pharmacokinetic and ECG data. In a virtual patient population, QTcF values were simulated for scenarios with and without concomitant clofazimine. ECG monitoring strategies to identify patients who need to interrupt treatment (QTcF > 500 ms) were explored. One hundred seventy patients were included, providing 1131 bedaquiline/M2 plasma concentrations and 1702 QTcF measurements; 2.1% of virtual patients receiving concomitant clofazimine had QTcF > 500 ms at any point during treatment (0.7% without concomitant clofazimine). With monthly monitoring, almost all patients with QTcF > 500 ms were identified by week 12; after week 12, patients were predominantly falsely identified as QTcF > 500 ms due to stochastic measurement error. Following a strategy with monitoring before treatment and at weeks 2, 4, 8, and 12 in simulations with concomitant clofazimine, 93.8% of all patients who should interrupt treatment were identified, and 26.4% of all interruptions were unnecessary (92.1% and 32.2%, respectively, without concomitant clofazimine). Our simulations enable an informed decision for a suitable ECG monitoring strategy by weighing the risk of missing patients with QTcF > 500 ms and that of interrupting bedaquiline treatment unnecessarily. We propose ECG monitoring before treatment and at weeks 2, 4, 8, and 12 after starting bedaquiline treatment.
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影响因子：
4.9
作者：
Ngwalero P;Brust JCM;van Beek SW;Wasserman S;Maartens G;Meintjes G;Joubert A;Norman J;Castel S;Gandhi NR;Denti P;McIlleron H;Svensson EM;Wiesner L
通讯作者：
Wiesner L
DOI：
10.1002/psp4.12722
发表时间：
2021-12
期刊：
CPT: pharmacometrics & systems pharmacology
影响因子：
--
作者：
Tanneau L;Svensson EM;Rossenu S;Karlsson MO
通讯作者：
Karlsson MO
DOI：
10.1093/jac/dkaa310
发表时间：
2020-11-01
期刊：
The Journal of antimicrobial chemotherapy
影响因子：
--
作者：
Abdelwahab MT;Wasserman S;Brust JCM;Gandhi NR;Meintjes G;Everitt D;Diacon A;Dawson R;Wiesner L;Svensson EM;Maartens G;Denti P
通讯作者：
Denti P
影响因子：
4.2
作者：
Isralls S;Baisley K;Ngam E;Grant AD;Millard J
通讯作者：
Millard J
影响因子：
6.4
作者：
Haas, David W.;Abdelwahab, Mahmoud Tareq;Brust, James C. M.
通讯作者：
Brust, James C. M.