Vongjarudech Thanakorn, Dosne Anne-Gaëlle, Remmerie Bart, Dooley Kelly E, Brust James C M, Maartens Gary, Meintjes Graeme, Karlsson Mats O, Svensson Elin M
Department of Pharmacy, Uppsala University, Uppsala, Sweden.
Janssen R&D, Beerse, Belgium.
Int J Antimicrob Agents. 2025 Apr;65(4):107460. doi: 10.1016/j.ijantimicag.2025.107460. Epub 2025 Feb 6.
Tachycardia associated with active tuberculosis (TB) often diminishes when patients recover from TB. Elevated heart rate (HR) may lead to suboptimal correction, complicating the assessment of QT prolongation when using standard correction factors (CFs), such as Fridericia's formula (QTcF). Olliaro has proposed a CF for QT interval correction in pretreatment TB patients. However, the QT-HR correlation changes as HR decreases during treatment, indicating the need for time-varying correction.
We developed an HR model to capture the HR normalisation during successful treatment. Subsequently, a time-varying CF was constructed using the estimated HR change rate. The performance of CFs to make corrected QT (QTc) independent from HR was evaluated by linear regression analyses of QTc versus HR within defined time bins.
The final HR model included asymptotic change in HR attributed to time on treatment, circadian rhythm cycles, M2 (bedaquiline-metabolite) concentration, and patient covariates. The time-varying CF decreased from 0.4081 to 0.33, with a half-life of 7.74 weeks. The slope (QTc/HR vs. Time) derived from the time-varying correction was not significantly different from 0 (95% CI -0.003 to 0.002), and the intercept was not significantly different from 0 (95% CI -0.089 to 0.006), demonstrating successful QT correction from pretreatment to the end of treatment.
The time-varying CF effectively captures the dynamic QT-HR relationship during TB treatment, reducing the risk of misdiagnosing QT prolongation or unnecessary discontinuation of treatment. By addressing underestimation and overestimation issues in QT interval assessment, this method enhances drug evaluation in clinical trials and supports improved treatment decisions for TB patients.
活动性肺结核（TB）相关的心动过速在患者从结核病康复时通常会减轻。心率（HR）升高可能导致校正不理想，在使用标准校正因子（CFs）（如弗里德里西亚公式（QTcF））时，会使QT延长的评估变得复杂。奥利亚罗提出了一种用于治疗前结核病患者QT间期校正的CF。然而，在治疗期间随着HR降低，QT-HR相关性会发生变化，这表明需要进行随时间变化的校正。
我们开发了一个HR模型来捕捉成功治疗期间HR的正常化。随后，使用估计的HR变化率构建了一个随时间变化的CF。通过在定义的时间区间内对QTc与HR进行线性回归分析，评估CFs使校正QT（QTc）与HR无关的性能。
最终的HR模型包括归因于治疗时间、昼夜节律周期、M2（贝达喹啉代谢物）浓度和患者协变量的HR渐近变化。随时间变化的CF从0.4081降至0.33，半衰期为7.74周。随时间变化的校正得出的斜率（QTc/HR与时间）与0无显著差异（95%CI -0.003至0.002），截距与0无显著差异（95%CI -0.089至0.006），表明从治疗前到治疗结束QT校正成功。
随时间变化的CF有效地捕捉了结核病治疗期间动态的QT-HR关系，降低了误诊QT延长或不必要停药的风险。通过解决QT间期评估中的低估和高估问题，该方法增强了临床试验中的药物评估，并支持改善结核病患者的治疗决策。
