在非人灵长类动物中评估作为前心律失常生物标志物的校正JT-峰值(JTpc)和Tpeak-to-Tend(TpTec):HESI 联合会的成果。

IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY Journal of pharmacological and toxicological methods Pub Date : 2024-07-15 DOI:10.1016/j.vascn.2024.107543
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引用次数: 0

摘要

导言校正 QT 间期(QTc)是药物诱发 Torsade de Pointe(TdP)的既定生物标志物,但存在假阳性信号的问题。在临床上,JTpc 和 TpTec 已成为心电图子区间,用于区分主要的 hERG 药物和延长 QTc 的混合离子通道阻滞药物:在一项多中心、前瞻性、对照研究中,使用导联 II 配置的内部和外部遥测技术,对猴子的 QTc、JTpc 和 TpTec 的不同促心律失常药物效应进行了表征:在猴子体内,多非利特(0.03-0.3 毫克/千克)与暴露依赖性 QTc 和 JTpc 升高有关,但对 TpTec 没有显著影响。同样,奎尼丁(2-50 毫克/千克)会增加 QTc 和 JTpc,但不会改变 TpTec。美西雷定(1-15 毫克/千克)和维拉帕米(50 毫克/千克)对 QTc、JTpc 或 TpTec 均无明显影响:讨论:临床上,主要的 hERG 阻滞剂(多非利特和奎尼丁)会延长 QTc、JTpc 和 TpTec,并增加 TdP 的风险。本研究结果表明,遥测猴服用多非利特和奎尼丁后的心电图变化与临床反应不同,对 TpTec 没有预期的影响。缺乏转化的潜在原因包括生理药理学物种差异或心电图记录和分析方法的差异。对猴子施用混合离子通道阻滞剂维拉帕米和美西律汀没有显示出明显的 QTc、JTpc 或 TpTec 延长,这是基于这两种药物类似的临床反应。
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Assessment of corrected JT-peak (JTpc) and Tpeak-to-Tend (TpTec) as proarrhythmia biomarkers in non-human primates: Outcome from a HESI consortium

Introduction

Corrected QT interval (QTc)is an established biomarker for drug-induced Torsade de Pointe (TdP), but with concerns for a false positive signal. Clinically, JTpc and TpTec have emerged as ECG sub-intervals to differentiate predominant hERG vs. mixed ion channel blocking drugs that prolong QTc.

Methods

In a multicentric, prospective, controlled study, different proarrhythmic drug effects on QTc, JTpc and TpTec were characterized with cynomolgus monkeys using telemetry in a Lead II configuration for internal and external telemetry.Drugs and vehicle were administered orally (PO) to group size of 4 to 8 animals, in 4 laboratories.

Results

In monkeys, dofetilide (0.03–0.3 mg/kg) was associated with exposure dependent QTc and JTpc increase, but no significant TpTec effect. Similarly, quinidine (2–50 mg/kg) increased QTc and JTpc but did not change TpTec. Mexiletine (1–15 mg/kg) and verapamil (50 mg/kg) did not induce any significant effect on QTc, JTpc or TpTec.

Discussion

Clinically, predominant hERG blockers (dofetilide and quinidine) prolong QTc, JTpc and TpTec and are associated with increased risk for TdP. Results from this study demonstrate that ECG changes after dofetilide and quinidine administration to telemetered monkeys differ from the clinical response, lacking the expected effects on TpTec. Potential explanations for the lack of translation include physio-pharmacology species differences or ECG recording and analysis methodology variations. Mixed ion channel blockers verapamil and mexiletine administered to monkeys showed no significant QTc, JTpc or TpTec prolongation as expected based on the similar clinical response for these agents.

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来源期刊
Journal of pharmacological and toxicological methods
Journal of pharmacological and toxicological methods PHARMACOLOGY & PHARMACY-TOXICOLOGY
CiteScore
3.60
自引率
10.50%
发文量
56
审稿时长
26 days
期刊介绍: Journal of Pharmacological and Toxicological Methods publishes original articles on current methods of investigation used in pharmacology and toxicology. Pharmacology and toxicology are defined in the broadest sense, referring to actions of drugs and chemicals on all living systems. With its international editorial board and noted contributors, Journal of Pharmacological and Toxicological Methods is the leading journal devoted exclusively to experimental procedures used by pharmacologists and toxicologists.
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