新药人体首次剂量设计的技术考虑

Considerations on the estimation of the starting dose design for a new drug in first-in-human study

确定人体首次(first in human,FIH)安全起始剂量是新药研发的关键步骤之一。多国监管机构发布了关于人体首次研究最大推荐起始剂量选择的指导性文件。基于非临床研究未见不良反应剂量(noobserved adverse effect level,NOAEL),以体表积标准化计算人体等效剂量,并根据试验药物特点等给予一定安全系数确定人体首次剂量的方法在药物开发领域广泛应用;基于最小预期生物效应剂量(minimal antici-pated biological effect level,MABEL)的人体首次剂量计算方法,综合了试验药物的PK/PD特性,以经验性总结和合理假设为基础建模和模拟,获得越来越多研发企业和监管机构的关注。本文旨在梳理FIH研究中最大推荐起始剂量(maximum recommended starting dose,MRSD)估算的规则,并以举例介绍常用的FIH剂量估算方法,对各种方法的适用性和优缺点进行讨论,为新药研发和评价提供实用参考。

To identify the safe starting dose of first-in-human is a critical step in drug development. Someguidance documents have been published by regulatory agencies of a number of countries. The method to estimatethe starting dose based on NOAEL from preclinical studies has been applied widely in drug development, which isnormalized by mg·m-2 and corrected by a safety factor according to the nature of an investigational drug. The attentionon the application of a MABEL-based method from both industry and agencies is increasing, which is based onempirical inductive and rational assumptions and may need modeling and simulation with the integrated PK/PDinformation. This review aims to clarify the basic rules to estimate the starting dose in FIH studies with the examplesof typical cases. The applicability, as well as relative merits and demerits of each method, was discussed to providea practical reference for drug development and evaluation.