Robison Timothy W, Jacobs Abigail
US FDA, Center for Drug Evaluation and Research, Office of New Drugs, 10993 New Hampshire Avenue, Silver Spring, MD 20993, USA.
Bioanalysis. 2009 Oct;1(7):1193-200. doi: 10.4155/bio.09.98.
Traditionally, only circulating concentrations of parent drug have been measured in the rodent and nonrodent test species used for drug safety assessments and served as an index of systemic exposure for comparisons to human exposures. Circulating concentrations of metabolites have generally only been measured in specialized circumstances (e.g., parent compound was extensively metabolized). Measurement of only the parent compound is usually sufficient when the metabolite profile in humans is similar to that in at least one of the animal species used in the nonclinical safety assessment. However, it is possible that metabolites formed in humans might not be present in the rodent and nonrodent test species used for drug safety assessments or the metabolites are formed at disproportionately higher concentrations in humans than in the animal test species. Generally, metabolites identified only in human plasma or metabolites present at disproportionately higher concentrations in humans than in any of the animal test species should be considered for safety assessment. The Center for Drug Evaluation and Research (CDER) published a Guidance for Industry on Safety Testing of Drug Metabolites that provides current thinking within CDER on the nonclinical safety assessment of human drug metabolites derived from drug products. The CDER guidance defines human metabolites that can raise a safety concern as those formed at greater than 10% of parent drug systemic exposure at a steady state. By contrast, the more recent International Conference on Harmonization: Guideline on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (ICH M3[R2]) describes the threshold as 10% of total drug-related exposure. Where they differ, the ICH guidance supersedes the CDER Guidance. The purpose of this article is to provide a perspective on the important details of these guidances from a regulatory review standpoint, as well as discuss some concerns that have arisen from the regulated industry regarding the CDER guidance. Such issues include parent drug that is extensively metabolized, metabolism by intestinal bacteria and metabolites formed by nonclinical test species but not humans.
传统上，在用于药物安全性评估的啮齿类和非啮齿类试验物种中，仅测定母体药物的循环浓度，并将其作为全身暴露的指标，用于与人体暴露情况进行比较。代谢物的循环浓度通常仅在特殊情况下进行测定（例如，母体化合物被广泛代谢）。当人类的代谢物谱与非临床安全性评估中使用的至少一种动物物种的代谢物谱相似时，仅测定母体化合物通常就足够了。然而，人类形成的代谢物可能不存在于用于药物安全性评估的啮齿类和非啮齿类试验物种中，或者这些代谢物在人类中的形成浓度与动物试验物种相比过高。一般来说，仅在人血浆中鉴定出的代谢物或在人类中浓度远高于任何动物试验物种的代谢物，都应进行安全性评估。药物评价和研究中心（CDER）发布了一份《药物代谢物安全性测试行业指南》，该指南提供了CDER目前对源自药品的人类药物代谢物的非临床安全性评估的思路。CDER指南将可能引起安全性担忧的人类代谢物定义为在稳态下形成的量超过母体药物全身暴露量10%的代谢物。相比之下，最近的国际协调会议：《药物临床试验和上市许可的非临床安全性研究指南》（ICH M3[R2]）将阈值描述为与药物相关的总暴露量的10%。两者存在差异时，ICH指南优先于CDER指南。本文的目的是从监管审查的角度对这些指南的重要细节提供一个观点，并讨论受监管行业对CDER指南提出的一些担忧。这些问题包括被广泛代谢的母体药物、肠道细菌的代谢作用以及非临床试验物种而非人类形成的代谢物。
