Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Sharp and Dohme Corp., West Point, Pennsylvania 19486, USA.
AAPS J. 2012 Sep;14(3):410-9. doi: 10.1208/s12248-012-9353-6. Epub 2012 Apr 7.
Thorough characterization and in-depth understanding of absorption, distribution, metabolism, and elimination (ADME) properties of a drug candidate have been well recognized as an important element in small molecule (SM) drug discovery and development. This has been the area of focus for drug metabolism and pharmacokinetics (DMPK) scientists, whose role has been evolving over the past few decades from primarily being involved in the development space after a preclinical candidate was selected to extending their involvement into the discovery stage prior to candidate selection. This paradigm shift has ensured the entry into development of the best candidates with optimal ADME properties, and thus has greatly impacted SM drug development through significant reduction of the failure rate for pharmacokinetics related reasons. In contrast, the sciences of ADME and DMPK have not been fully integrated into the discovery and development processes for large molecule (LM) drugs. In this mini-review, we reflect on the journey of DMPK support of SM drug discovery and development and highlight the key enablers that have allowed DMPK scientists to make such impacts, with the aim to provide a perspective on relevant lessons learned from SM drugs that are applicable to DMPK support strategies for LMs.
透彻的表征和深入理解候选药物的吸收、分布、代谢和消除（ADME）性质已被公认为小分子（SM）药物发现和开发的重要元素。这一直是药物代谢和药代动力学（DMPK）科学家关注的焦点，他们的角色在过去几十年中发生了演变，从主要在临床前候选药物选定后参与开发领域，扩展到在候选药物选定前就参与发现阶段。这种范式转变确保了具有最佳 ADME 性质的最佳候选药物进入开发阶段，从而通过大大降低因药代动力学相关原因而导致的失败率，极大地影响了 SM 药物的开发。相比之下，ADME 和 DMPK 科学尚未完全融入大分子（LM）药物的发现和开发过程中。在这篇迷你综述中，我们反思了 DMPK 对 SM 药物发现和开发的支持历程，并强调了使 DMPK 科学家能够产生如此影响的关键促成因素，以期提供从 SM 药物中吸取的相关经验教训，这些经验教训适用于 LM 的 DMPK 支持策略。
