Exposure-safety analysis of QTc interval and transaminase levels following bedaquiline administration in patients with drug-resistant tuberculosis.
Exposure-safety analysis of QTc interval and transaminase levels following bedaquiline administration in patients with drug-resistant tuberculosis.
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DOI：
10.1002/psp4.12722
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Karlsson MO
中科院分区：
文献类型：
--
作者：
Tanneau L;Svensson EM;Rossenu S;Karlsson MO
近年来，贝达喹啉（BDQ）在治疗耐多药结核病（MDR - TB）方面显示出巨大的价值。然而，必须探索暴露与安全的关系，以扩大BDQ的使用。据报道，BDQ的两个安全性发现是QTc间隔延长和转氨酶水平升高。在这项研究中，我们调查了使用批准剂量方案的MDR - TB患者BDQ和/或其主要代谢物（M2）药代动力学（PK）指标和QTcF间隔或转氨酶水平之间的潜在关系。通过非线性混合效应模型分析了来自两项IIb期研究的429例MDR - TB患者的数据。在QTcF间隔和转氨酶水平暴露-反应模型中，分别评估了个体模型预测浓度和总结PK指标。在两个模型中对进一步的协变量效应进行了调查。在一个考虑昼夜节律模式、研究时间、伴随用药与QT间期倾向性的影响和患者人口统计学的模型中，M2浓度被发现与药物相关的QTcF增加有关。最终模型的模拟表明，高于批准剂量（导致M2浓度增加）的剂量预计不会导致临界QTcF间隔增加。尽管先前有报道称接受BDQ治疗的患者转氨酶水平较高，但转氨酶水平与暴露-安全之间没有关系。所开发的纵向模型表征了M2浓度在QTc间隔延长中的作用，并发现转氨酶水平升高不依赖于浓度，这表明在观察范围的高端BDQ暴露可能与更高的安全事件风险无关。
Bedaquiline (BDQ) has shown great value in the treatment of multidrug‐resistant tuberculosis (MDR‐TB) in recent years. However, exposure–safety relationships must be explored to extend the use of BDQ. Two reported safety findings for BDQ are prolongation of the QTc interval and elevation of transaminase levels. In this study, we investigated the potential relationships between BDQ and/or its main metabolite (M2) pharmacokinetic (PK) metrics and QTcF interval or transaminase levels in patients with MDR‐TB using the approved dose regimen. Data from 429 patients with MDR‐TB from two phase IIb studies were analyzed via nonlinear mixed‐effects modeling. Individual model‐predicted concentrations and summary PK metrics were evaluated, respectively, in the QTcF interval and transaminase level exposure–response models. Investigation of further covariate effects was performed in both models. M2 concentrations were found to be responsible for the drug‐related QTcF increase in a model accounting for circadian rhythm patterns, time on study, effect of concomitant medication with QT liability, and patient demographics. Simulations with the final model suggested that doses higher than the approved dose (leading to increased M2 concentrations) are not expected to lead to a critical QTcF interval increase. No exposure–safety relationship could be described with transaminase levels despite previous reports of higher levels in patients treated with BDQ. The developed longitudinal models characterized the role of M2 concentrations in QTc interval prolongation and found no concentration dependency for transaminase level elevation, together suggesting that BDQ exposure at the high end of the observed range may not be associated with a higher risk of safety events.
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影响因子：
4.9
作者：
Svensson, Elin M.;Dooley, Kelly E.;Karlsson, Mats O.
通讯作者：
Karlsson, Mats O.
影响因子：
24.3
作者：
Pym, Alexander S.;Diacon, Andreas H.;Dannemann, Brian
通讯作者：
Dannemann, Brian
DOI：
10.5588/ijtld.17.0706
发表时间：
2018-04-01
影响因子：
4
作者：
Cox, V;Brigden, G.;Furin, J.
通讯作者：
Furin, J.
DOI：
10.5588/ijtld.17.0615
发表时间：
2018-01-01
影响因子：
4
作者：
Maartens, G.;Brill, M. J. E.;Svensson, E. M.
通讯作者：
Svensson, E. M.
影响因子：
3.4
作者：
Tanneau, Lenaig;Karlsson, Mats O.;Svensson, Elin M.
通讯作者：
Svensson, Elin M.