Wiśniowska Barbara, Tylutki Zofia, Wyszogrodzka Gabriela, Polak Sebastian
Unit of Pharmacoepidemiology and Pharmacoeconomics, Department of Social Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 Street, 30-688, Krakow, Poland.
Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Medical College, Jagiellonian University, Medyczna 9 Street, 30-688, Kraków, Poland.
BMC Pharmacol Toxicol. 2016 Mar 10;17:12. doi: 10.1186/s40360-016-0053-1.
Proarrhythmia assessment is one of the major concerns for regulatory bodies and pharmaceutical industry. ICH guidelines recommending preclinical tests have been established in attempt to eliminate the risk of drug-induced arrhythmias. However, in the clinic, arrhythmia occurrence is determined not only by the inherent property of a drug to block ion currents and disturb electrophysiological activity of cardiac myocytes, but also by many other factors modifying individual risk of QT prolongation and subsequent proarrhythmia propensity. One of those is drug-drug interactions. Since polypharmacy is a common practice in clinical settings, it can be anticipated that there is a relatively high risk that the patient will receive at least two drugs mutually modifying their proarrhythmic potential and resulting either in triggering the occurrence or mitigating the clinical symptoms. The mechanism can be observed either directly at the pharmacodynamic level by competing for the molecular targets, or indirectly by modifying the physiological parameters, or at the pharmacokinetic level by alteration of the active concentration of the victim drug.
This publication provides an overview of published clinical studies on pharmacokinetic and/or pharmacodynamic drug-drug interactions in humans and their electrophysiological consequences (QT interval modification). Databases of PubMed and Scopus were searched and combinations of the following keywords were used for Title, Abstract and Keywords fields: interaction, coadministration, combination, DDI and electrocardiographic, QTc interval, ECG. Only human studies were included. Over 4500 publications were retrieved and underwent preliminary assessment to identify papers accordant with the topic of this review. 76 papers reporting results for 96 drug combinations were found and analyzed.
The results show the tremendous variability of drug-drug interaction effects, which makes one aware of complexity of the problem, and suggests the need for assessment of an additional risk factors and careful ECG monitoring before administration of drugs with anticipated QT prolongation.
DDIs can play significant roles in drugs' cardiac safety, as evidenced by the provided examples. Assessment of the pharmacodynamic effects of the drug interactions is more challenging as compared to the pharmacokinetic due to the significant diversity in the endpoints which should be analyzed specifically for various clinical effects. Nevertheless, PD components of DDIs should be accounted for as PK changes alone do not allow to fully explain the electrophysiological effects in clinic situations.
致心律失常性评估是监管机构和制药行业主要关注的问题之一。已制定了国际人用药品注册技术协调会（ICH）指南推荐的临床前试验，试图消除药物诱发心律失常的风险。然而，在临床中，心律失常的发生不仅取决于药物阻断离子电流和干扰心肌细胞电生理活动的固有特性，还取决于许多其他因素，这些因素会改变个体QT间期延长的风险以及随后的致心律失常倾向。其中一个因素就是药物相互作用。由于联合用药在临床环境中很常见，可以预计患者接受至少两种相互改变其致心律失常潜能的药物的风险相对较高，这可能导致心律失常的发生或减轻临床症状。这种机制可以在药效学水平上通过竞争分子靶点直接观察到，也可以通过改变生理参数间接观察到，或者在药代动力学水平上通过改变受影响药物的活性浓度观察到。
本出版物概述了已发表的关于人体药代动力学和/或药效学药物相互作用及其电生理后果（QT间期改变）的临床研究。检索了PubMed和Scopus数据库，并在标题、摘要和关键词字段中使用了以下关键词组合：相互作用、联合给药、组合、药物相互作用（DDI）以及心电图、QTc间期、心电图（ECG）。仅纳入人体研究。检索到4500多篇出版物，并进行了初步评估，以确定符合本综述主题的论文。发现并分析了76篇报告96种药物组合结果的论文。
结果显示药物相互作用效应存在巨大差异，这让人意识到该问题的复杂性，并表明在使用预期会延长QT间期的药物之前，需要评估额外的风险因素并进行仔细的心电图监测。
正如所举例子所示，药物相互作用在药物心脏安全性方面可发挥重要作用。与药代动力学相比，评估药物相互作用的药效学效应更具挑战性，因为终点存在显著差异，应针对各种临床效应进行具体分析。然而，药物相互作用的药效学成分应予以考虑，因为仅药代动力学变化无法完全解释临床情况下的电生理效应。
