Meid Andreas D, Bighelli Irene, Mächler Sarah, Mikus Gerd, Carrà Giuseppe, Castellazzi Mariasole, Lucii Claudio, Martinotti Giovanni, Nosè Michela, Ostuzzi Giovanni, Barbui Corrado, Haefeli Walter E
Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
WHO Collaborating Center for Research and Training in Mental Health and Service Evaluation, University of Verona, Verona, Italy.
Ther Adv Psychopharmacol. 2017 Dec;7(12):251-264. doi: 10.1177/2045125317721662. Epub 2017 Aug 28.
Whether arrhythmia risks will increase if drugs with electrocardiographic (ECG) QT-prolonging properties are combined is generally supposed but not well studied. Based on available evidence, the Arizona Center for Education and Research on Therapeutics (AZCERT) classification defines the risk of QT prolongation for exposure to single drugs. We aimed to investigate how combining AZCERT drug categories impacts QT duration and how relative drug exposure affects the extent of pharmacodynamic drug-drug interactions.
In a cohort of 2558 psychiatric inpatients and outpatients, we modeled whether AZCERT class and number of coprescribed QT-prolonging drugs correlates with observed rate-corrected QT duration (QTc) while also considering age, sex, inpatient status, and other QTc-prolonging risk factors. We concurrently considered administered drug doses and pharmacokinetic interactions modulating drug clearance to calculate individual weights of relative exposure with AZCERT drugs. Because QTc duration is concentration-dependent, we estimated individual drug exposure with these drugs and included this information as weights in weighted regression analyses.
Drugs attributing a 'known' risk for clinical consequences were associated with the largest QTc prolongations. However, the presence of at least two one QTc-prolonging drug yielded nonsignificant prolongations [exposure-weighted parameter estimates with 95% confidence intervals for 'known' risk drugs + 0.93 ms (-8.88;10.75)]. Estimates for the 'conditional' risk class increased upon refinement with relative drug exposure and co-administration of a 'known' risk drug as a further risk factor.
These observations indicate that indiscriminate combinations of QTc-prolonging drugs do not necessarily result in additive QTc prolongation and suggest that QT prolongation caused by drug combinations strongly depends on the nature of the combination partners and individual drug exposure. Concurrently, it stresses the value of the AZCERT classification also for the risk prediction of combination therapies with QT-prolonging drugs.
一般认为，具有心电图（ECG）QT 间期延长特性的药物联合使用时心律失常风险是否会增加，但尚未得到充分研究。基于现有证据，亚利桑那治疗学教育与研究中心（AZCERT）分类定义了单一药物暴露的 QT 间期延长风险。我们旨在研究联合使用 AZCERT 药物类别如何影响 QT 间期，以及相对药物暴露如何影响药效学药物相互作用的程度。
在一组 2558 名精神科住院患者和门诊患者中，我们建立模型，研究 AZCERT 类别和联合使用的 QT 间期延长药物数量是否与观察到的校正心率 QT 间期（QTc）相关，同时考虑年龄、性别、住院状态和其他 QTc 延长风险因素。我们同时考虑给药剂量和调节药物清除的药代动力学相互作用，以计算 AZCERT 药物的相对暴露个体权重。由于 QTc 间期是浓度依赖性的，我们估计这些药物的个体药物暴露，并将此信息作为权重纳入加权回归分析。
具有“已知”临床后果风险的药物与最大的 QTc 间期延长相关。然而，至少两种——一种 QT 间期延长药物的存在导致延长不显著[“已知”风险药物的暴露加权参数估计值及 95%置信区间为+0.93 毫秒（-8.88；10.75）]。随着相对药物暴露的细化以及将一种“已知”风险药物的联合使用作为进一步风险因素，“条件性”风险类别的估计值增加。
这些观察结果表明，QT 间期延长药物的随意联合使用不一定会导致 QTc 间期延长相加，并表明药物联合导致的 QT 间期延长强烈依赖于联合用药伙伴的性质和个体药物暴露。同时，这强调了 AZCERT 分类对于 QT 间期延长药物联合治疗风险预测的价值。
