Department of Clinical Pharmacology, Pfizer Global Research and Development, 10555 Science Center Drive, San Diego, CA 92121, USA.
AAPS J. 2013 Apr;15(2):551-8. doi: 10.1208/s12248-013-9464-8. Epub 2013 Feb 14.
The industry-wide biopharmaceutical (i.e., biologic, biotherapeutic) pipeline has been growing at an astonishing rate over the last decade with the proportion of approved new biological entities to new chemical entities on the rise. As biopharmaceuticals appear to be growing in complexity in terms of their structure and mechanism of action, so are interpretation, analysis, and prediction of their quantitative pharmacology. We present here a modeling and simulation (M&S) framework for the successful preclinical development of monoclonal antibodies (as an illustrative example of biopharmaceuticals) and discuss M&S strategies for its implementation. Critical activities during early discovery, lead optimization, and the selection of starting doses for the first-in-human study are discussed in the context of pharmacokinetic-pharmacodynamic (PKPD) and M&S. It was shown that these stages of preclinical development are and should be reliant on M&S activities including systems biology (SB), systems pharmacology (SP), and translational pharmacology (TP). SB, SP, and TP provide an integrated and rationalized framework for decision making during the preclinical development phase. In addition, they provide increased target and systems understanding, describe and interpret data generated in vitro and in vivo, predict human PKPD, and provide a rationalized approach to designing the first-in-human study.
过去十年中,整个行业的生物制药(即生物制剂、生物疗法)管道以惊人的速度增长,批准的新型生物实体与新型化学实体的比例不断上升。随着生物制药在结构和作用机制方面似乎变得越来越复杂,对其定量药理学的解释、分析和预测也变得越来越复杂。我们在此提出了一种建模和模拟 (M&S) 框架,用于成功进行单克隆抗体的临床前开发(作为生物制药的一个示例),并讨论了实施该框架的 M&S 策略。在药代动力学-药效学 (PKPD) 和 M&S 的背景下,讨论了早期发现、先导优化以及首次人体研究起始剂量选择过程中的关键活动。结果表明,这些临床前开发阶段依赖于 M&S 活动,包括系统生物学 (SB)、系统药理学 (SP) 和转化药理学 (TP)。SB、SP 和 TP 为临床前开发阶段的决策提供了一个集成和合理化的框架。此外,它们还提供了对目标和系统的更深入理解,描述和解释了在体外和体内产生的数据,预测了人体 PKPD,并为设计首次人体研究提供了合理化的方法。