Clinical Pharmacology and DMPK, AstraZeneca R&D Södertälje, Södertälje, Sweden.
Clin Pharmacol Ther. 2010 Oct;88(4):532-9. doi: 10.1038/clpt.2010.131. Epub 2010 Sep 1.
In order to evaluate their potential effects on cardiac repolarization, all new drugs must undergo clinical electrocardiographic evaluation in a thorough QT/QTc (TQT) study. AZD3480, a central nervous system-selective, neuronal nicotinic receptor (NNR) agonist, is predominantly metabolized by cytochrome P450 2D6 (CYP2D6). Employing an innovative design, this TQT study assessed the effects of supratherapeutic doses of AZD3480, relative to those of placebo, on cardiac repolarization in healthy male volunteers genotyped as either poor metabolizers (PMs) or extensive metabolizers (EMs) of CYP2D6 substrates. Supratherapeutic doses of AZD3480-resulting in ~10- and ~50-fold higher exposures (PMs and EMs, respectively) than achieved with a 20-mg dose-had no pharmacologic effect on cardiac repolarization relative to placebo. Likewise, no safety/tolerability concerns were observed after either supratherapeutic or 20-mg dosing to either population. No clinically relevant treatment-related changes or trends were observed in laboratory parameters, vital signs, or electrocardiogram (ECG). This study demonstrated that AZD3480 does not prolong QT/QTc interval.
为了评估它们对心脏复极的潜在影响，所有新药都必须在全面的 QT/QTc（TQT）研究中进行临床心电图评估。AZD3480 是一种中枢神经系统选择性、神经元烟碱受体（NNR）激动剂，主要由细胞色素 P450 2D6（CYP2D6）代谢。这项 TQT 研究采用创新设计，评估了相对于安慰剂，CYP2D6 底物的代谢不良者（PM）或广泛代谢者（EM）接受 AZD3480 超治疗剂量对健康男性志愿者心脏复极的影响。AZD3480 的超治疗剂量导致的暴露水平分别比 20mg 剂量高约 10 倍和 50 倍（PM 和 EM 分别），与安慰剂相比，对心脏复极没有药理作用。同样，在超治疗剂量或 20mg 剂量给药后，两种人群均未观察到安全性/耐受性问题。实验室参数、生命体征或心电图（ECG）均未观察到与治疗相关的有临床意义的变化或趋势。这项研究表明，AZD3480 不会延长 QT/QTc 间期。
