Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA.
Expert Opin Drug Metab Toxicol. 2010 Dec;6(12):1539-49. doi: 10.1517/17425255.2010.530655. Epub 2010 Nov 11.
The FDA and the International Conference on Harmonization (ICH) recently issued regulatory guidance on metabolites in safety testing (MIST). One of the key differences between these two types of guidance is the threshold for a major metabolite: > 10% of AUC of the parent drug at steady-state (the FDA) versus > 10% of drug-related exposure (ICH). The FDA agreed to adopt the ICH M3 threshold in 2010. Both guidance require metabolite profiling in humans during early clinical development which have presented significant challenges from two aspects: i) how to balance the recommendation of front-loading of metabolism studies with the need to invest resources appropriately according to the stage of drug development and ii) how to fully utilize alternative bioanalytical approaches to generate reliable data for enabling prompt and informed decisions, without always resorting to resource-intensive good laboratory practices bioanalysis.
This review summarizes current thinking in the pharmaceutical industry on these two aspects.
this review aims to provide the reader with a clear understanding of the importance and timing of various metabolism studies and an overview of the latest bioanalytical approaches of quantitation of metabolites in the absence of reference standards.
the approaches outlined are not intended to be universal solutions to MIST. The researcher still has to consider a case-by-case approach with scientific justification to comply with the MIST guidance.
美国食品和药物管理局（FDA）和国际人用药品注册技术协调会（ICH）最近发布了关于安全测试中代谢物（MIST）的监管指南。这两种指南的一个关键区别是主要代谢物的阈值：稳态时母体药物 AUC 的>10%（FDA）与药物相关暴露的>10%（ICH）。FDA 于 2010 年同意采用 ICH M3 阈值。这两种指南都要求在早期临床开发期间对人体中的代谢物进行分析，这在两个方面带来了重大挑战：i）如何在根据药物开发阶段适当投入资源的需要与代谢研究前端加载的建议之间取得平衡，以及 ii）如何充分利用替代生物分析方法来生成可靠数据，以便能够迅速做出明智的决策，而不必总是依赖资源密集型的良好实验室规范生物分析。
本篇综述总结了制药行业在这两个方面的当前思路。
本篇综述旨在使读者清楚地了解各种代谢研究的重要性和时间安排，并概述在没有参比标准的情况下定量代谢物的最新生物分析方法。
概述的方法并非旨在成为 MIST 的通用解决方案。研究人员仍需根据具体情况进行科学论证，以符合 MIST 指南。
