Comparison of validity of standard nonclinical group size selection versus standard clinical group sizes for nonhuman primate QTc prolongation evaluation

IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY
David Holdsworth , Derek D. Best , Katarina Haist , Kyle O'Donohue , Anson Phillips , Matthew M. Abernathy , Brian Roche , Derek J. Leishman
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引用次数: 5

Abstract

The number of animals used in a nonhuman primate (NHP) in vivo QTc assessment conducted as part of the safety pharmacology (SP) studies on a potential new drug is relatively small (4–8 subjects). The number is much smaller than the number of healthy volunteers in a conventional thorough QT (TQT) study (40–60 volunteers). How is it possible that such small studies could offer an equivalent sensitivity in an integrated nonclinical and clinical cardiac repolarization risk assessment?

This study provided the opportunity to empirically demonstrate in a large number of NHPs the performance of a nonclinical evaluation at a similar size to a TQT study.

By contrasting an analysis mimicking the sampling and aggregation of QTc interval data in a manner which is TQT-like with a more conventional SP-like analysis it was demonstrated that the SP-like analysis was more sensitive. In prospective power calculations 80% power at p = 0.05 can be achieved for a 5 ms QTc change with only n = 8 NHPs using the SP-like analysis and in a group of only 4 NHPs 80% power to detect 10 ms could be achieved. By contrast groups of 24 NHPs would be required to achieve 80% power to detect 5 ms using the TQT-like sampling and aggregation approach.

Overall, this study has demonstrated that smaller safety pharmacology in vivo QTc assessments using all the available data in larger data aggregates can achieve sensitivity comparable to a human TQT study.

非人灵长类动物QTc延长评估的标准非临床群体大小选择与标准临床群体大小的有效性比较
作为潜在新药安全药理学(SP)研究的一部分,用于非人灵长类动物(NHP)体内QTc评估的动物数量相对较少(4-8个受试者)。这个数字远远小于传统的全面QT (TQT)研究中健康志愿者的数量(40-60名志愿者)。这么小的研究怎么可能在综合的非临床和临床心脏复极风险评估中提供同等的敏感性?本研究提供了一个机会,在大量的NHPs中实证证明了与TQT研究规模相似的非临床评估的表现。通过对比以类似tqt的方式模拟QTc区间数据的采样和聚合的分析,与更传统的类似sp的分析相比,表明类似sp的分析更敏感。在前瞻性功率计算中,使用类似sp的分析,在只有n = 8个NHPs的情况下,对于5 ms QTc变化,在p = 0.05时可以获得80%的功率,而在只有4个NHPs的情况下,可以获得80%的功率来检测10 ms。相比之下,使用类似tqt的采样和聚合方法,需要24个NHPs组才能达到80%的功率来检测5 ms。总的来说,这项研究表明,使用所有可用数据进行更大数据集的体内QTc安全性药理学评估可以达到与人类TQT研究相当的灵敏度。
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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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