Hall Michael P
Department of Pharmacokinetics & Drug Metabolism, Amgen Inc., Thousand Oaks, California
Drug Metab Dispos. 2014 Nov;42(11):1873-80. doi: 10.1124/dmd.114.058347. Epub 2014 Jun 19.
Historically, since the metabolism of administered peptide/protein drugs ("biotherapeutics") has been expected to undergo predictable pathways similar to endogenous proteins, comprehensive biotherapeutic metabolism studies have not been widely reported in the literature. However, since biotherapeutics have rapidly evolved into an impressive array of eclectic modalities, there has been a shift toward understanding the impact of metabolism on biotherapeutic development. For biotherapeutics containing non-native chemical linkers and other moieties besides natural amino acids, metabolism studies are critical as these moieties may impart undesired toxicology. For biotherapeutics that are composed solely of natural amino acids, where end-stage peptide and amino acid catabolites do not generally pose toxicity concerns, the understanding of biotherapeutic biotransformation, defined as in vivo modifications such as peripherally generated intermediate circulating catabolites prior to end-stage degradation or elimination, may impact in vivo stability and potency/clearance. As of yet, there are no harmonized methodologies for understanding biotherapeutic biotransformation and its impact on drug development, nor is there clear guidance from regulatory agencies on how and when these studies should be conducted. This review provides an update on biotherapeutic biotransformation studies and an overview of lessons learned, tools that have been developed, and suggestions of approaches to address issues. Biotherapeutic biotransformation studies, especially for certain modalities, should be implemented at an early stage of development to 1) understand the impact on potency/clearance, 2) select the most stable candidates or direct protein re-engineering efforts, and 3) select the best bioanalytical technique(s) for proper drug quantification and subsequent pharmacokinetic profiling and exposure/response assessment.
从历史上看，由于人们预期施用的肽/蛋白质药物（“生物治疗药物”）的代谢会经历与内源性蛋白质相似的可预测途径，因此全面的生物治疗药物代谢研究在文献中并未得到广泛报道。然而，由于生物治疗药物已迅速发展成为一系列令人印象深刻的折衷模式，人们的关注点已转向了解代谢对生物治疗药物开发的影响。对于含有非天然化学连接子和除天然氨基酸之外的其他部分的生物治疗药物，代谢研究至关重要，因为这些部分可能会产生不良毒理学影响。对于仅由天然氨基酸组成的生物治疗药物，终末期肽和氨基酸代谢产物通常不会引起毒性问题，而对生物治疗药物生物转化（定义为体内修饰，如在终末期降解或消除之前在外周产生的中间循环代谢产物）的了解可能会影响体内稳定性和效力/清除率。截至目前，尚无统一的方法来了解生物治疗药物的生物转化及其对药物开发的影响，监管机构也没有关于如何以及何时进行这些研究的明确指导。本综述提供了生物治疗药物生物转化研究的最新情况，概述了所吸取的经验教训、已开发的工具以及解决问题的方法建议。生物治疗药物生物转化研究，尤其是针对某些模式的研究，应在开发的早期阶段进行，以：1）了解对效力/清除率的影响；2）选择最稳定的候选药物或指导蛋白质重新工程努力；3）选择最佳的生物分析技术，以进行适当的药物定量以及后续的药代动力学分析和暴露/反应评估。
