IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY Journal of Pharmacology and Experimental Therapeutics Pub Date : 2025-02-01 Epub Date: 2024-11-22 DOI:10.1124/jpet.124.002184
Atsushi Sugiyama, Ai Goto, Hiroko Izumi-Nakaseko, Yoshinori Takei, Akira Takahara, Ryuichi Kambayashi
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引用次数: 0

摘要

国际人用药品技术要求协调理事会(ICH)于 2005 年制定了 S7B 和 E14 指南,以预防药物诱发的心搏骤停(TdP),从而有效地防止了高风险药物的开发。然而,这些指南阻碍了一些具有潜在价值的候选药物的开发,尽管它们尚未被证实具有促心律失常作用。为此,2013 年提出了全面的体外原发性心律失常检测和暴露-反应模型,以加强原发性心律失常风险评估。2022 年,ICH 发布了 E14/S7B 问题与解答(第 1 阶段),强调了低风险化合物的 "双阴性 "非临床情景。对于 "非双阴性 "化合物,预计不久将颁布新的问题和答案作为第 2 阶段,届时将提供有关原发性心律失常模型和原发性心律失常替代标记物的更详细建议。本综述详细介绍了药物诱发 TdP 的发病机制,包括 IKr 抑制、药代动力学因素、自主神经调节和再极化储备减少。除 QT 间期外,本综述还探讨了促心律失常替代标记物(J-峰值、T-峰值-终值和终末复极期)的效用。最后,报告介绍了各种用于预测前心律失常风险的体外、体内和体外硅学模型,如体外前心律失常综合测试硅学模型、诱导多能干细胞衍生心肌细胞片、朗根多夫灌注心脏制备、慢性房室传导阻滞动物(狗、猴、猪和兔)、急性房室传导阻滞兔、甲氧胺致敏兔以及针对特定长 QT 综合征的基因工程兔。这些模型和替代标记物可在量化新化合物的 TdP 风险、影响后期临床设计和监管决策以及预防上市后临床使用中的不良事件方面发挥重要作用。意义声明:由于 ICH S7B/E14 指南阻碍了一些具有潜在价值但未证实有致心律失常风险的化合物的开发,因此 2013 年提出了全面的体外致心律失常检测和暴露-反应模型,以加强对新化合物的致心律失常风险评估。2022 年,ICH 发布了问题和答案(第 1 阶段),强调了低风险化合物的 "双阴性 "非临床情景,预计还将针对 "非双阴性 "化合物发布新的问题和答案(第 2 阶段)。本综述深入探讨了替代标记物导致心律失常的机制,并探讨了预测导致心律失常风险的各种模型。
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Drug-induced long QT syndrome: Concept and nonclinical models for predicting the onset of drug-induced torsade de pointes in patients in compliance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E14/S7B guidance.

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) established S7B and E14 guidelines in 2005 to prevent drug-induced torsade de pointes (TdP), effectively preventing the development of high-risk drugs. However, those guidelines hampered the development of some potentially valuable drug candidates despite not being proven to be proarrhythmic. In response, comprehensive in vitro proarrhythmia assay and exposure-response modeling were proposed in 2013 to reinforce proarrhythmic risk assessment. In 2022, the ICH released E14/S7B questions and answers (stage 1), emphasizing a "double negative" nonclinical scenario for low-risk compounds. For "non-double negative" compounds, new questions and answers are expected to be enacted as stage 2 shortly, in which more detailed recommendations for proarrhythmia models and proarrhythmic surrogate markers will be provided. This review details the onset mechanisms of drug-induced TdP, including IKr inhibition, pharmacokinetic factors, autonomic regulation, and reduced repolarization reserve. It also explores the utility of proarrhythmic surrogate markers (J-Tpeak, Tpeak-Tend, and terminal repolarization period) besides QT interval. Finally, it presents various in silico, in vitro, ex vivo, and in vivo models for proarrhythmic risk prediction, such as comprehensive in vitro proarrhythmia assay in silico model, induced pluripotent stem cell-derived cardiomyocyte sheet, Langendorff-perfused heart preparation, chronic atrioventricular block animals (dogs, monkeys, pigs, and rabbits), acute atrioventricular block rabbits, methoxamine-sensitized rabbits, and genetically engineered rabbits for specific long QT syndromes. Those models along with the surrogate markers can play important roles in quantifying TdP risk of new compounds, impacting late-phase clinical design and regulatory decision-making, and preventing adverse events on postmarketing clinical use. SIGNIFICANCE STATEMENT: Since ICH S7B/E14 guidelines hampered the development of some potentially valuable compounds with unproven proarrhythmic risk, comprehensive in vitro proarrhythmia assay and exposure-response modeling were proposed in 2013 to reinforce proarrhythmic risk assessment of new compounds. In 2022, the ICH released questions and answers (stage 1), emphasizing a "double negative" nonclinical scenario for low-risk compounds, and new questions and answers (stage 2) for "non-double negative" compounds are expected. This review delves into proarrhythmic mechanisms with surrogate markers and explores various models for proarrhythmic risk prediction.

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来源期刊
CiteScore
6.90
自引率
0.00%
发文量
115
审稿时长
1 months
期刊介绍: A leading research journal in the field of pharmacology published since 1909, JPET provides broad coverage of all aspects of the interactions of chemicals with biological systems, including autonomic, behavioral, cardiovascular, cellular, clinical, developmental, gastrointestinal, immuno-, neuro-, pulmonary, and renal pharmacology, as well as analgesics, drug abuse, metabolism and disposition, chemotherapy, and toxicology.
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