Department of Drug Disposition, Lilly Research Laboratories, Indianapolis, IN 46285, USA.
Expert Opin Drug Metab Toxicol. 2012 Aug;8(8):985-97. doi: 10.1517/17425255.2012.693159. Epub 2012 Jun 10.
An evolution in bioanalytical methodologies to identify and quantify drug metabolites has led to a wealth of biotransformation information during preclinical and early clinical testing phases. However, this abundance of metabolism data has not clarified how to select the most important circulating human metabolites for safety assessment. Consequently, more stringent regulatory expectations for a comprehensive approach to human metabolism have led pharmaceutical sponsors to employ a variety of novel methods to estimate circulating drug metabolites in humans and animals.
This review provides context for 'why' human circulating metabolites must be qualified for safety in animals. A detailed overview is also presented concerning 'where,' 'how' and 'when' to conduct these assessments during drug development.
A human metabolite qualification strategy is now a required element of the drug safety package submitted with a new drug application (NDA). The important question is whether or not this additional information, about metabolite safety, is making human drugs any safer. Currently, this is a debatable issue, especially because stand-alone metabolite testing is fraught with its own challenges. As drug development moves into the twenty-first century, there is a pressing need for more sophisticated methodologies to address human drug and metabolite safety.
生物分析方法的发展使得在临床前和早期临床试验阶段能够识别和定量药物代谢物，从而产生了大量的生物转化信息。然而，这些丰富的代谢数据并没有阐明如何选择最重要的循环人体代谢物进行安全性评估。因此，监管机构对全面评估人体代谢的期望更加严格，这导致制药商采用了各种新方法来估计人体和动物中循环药物代谢物。
本综述为“为什么”必须对动物中的循环人体代谢物进行定性以确保安全性提供了背景。还详细介绍了在药物开发过程中何时、何地以及如何进行这些评估。
目前，人类代谢物鉴定策略已成为新药申请（NDA）提交的药物安全方案的必要组成部分。重要的问题是，关于代谢物安全性的这些额外信息是否使人类药物更安全。目前，这是一个有争议的问题，特别是因为单独的代谢物测试本身就充满了挑战。随着药物开发进入 21 世纪，迫切需要更复杂的方法来解决人类药物和代谢物的安全性问题。
