摘要
近年来,重组蛋白多肽和蛋白质已发展成为主流药物。多肽和蛋白类药物在临床前和临床研究以及治疗用药中均占有相当大的比重。理解药物动力学和药效动力学,包括剂量-浓度-效应之间的关系,对于包括多肽和蛋白类在内的任何药物都是至关重要的,因为它奠定了优化给药方案和临床合理用药的基础。比起传统的基于小分子的疗法,多肽和蛋白类药物的药物暴露/效应评价往往由于下列因素而变得复杂:(1)与内源性多肽、蛋白及营养物质的相似性;(2)能在分子水平直接参与体内生理过程;(3)具有高分子特性及免疫原性;(4)由于存在着很多相似的分子,目标物的分析和量化具有一定的挑战性。不像传统的小分子药物,多肽和蛋白质口服后往往没有治疗活性。为选择最适当的给药途径,需要全面了解多肽和蛋白质理化性质以外的吸收特性,包括化学和代谢稳定性、吸收部位、免疫反应性、跨膜过程以及主动摄取和外排过程。肽和蛋白质的各种分布特性决定了其在靶器官能否达到适宜浓度从而发挥预期疗效,而结合现象和受体介导的细胞摄取有可能使这个问题更加复杂化。消除过程作为药物全身暴露的一个关键因素,可以是众多通路的综合,包括肾脏及肝脏代谢通路以及广义的蛋白水解作用与受体介导的内吞作用。多肽和蛋白质为基础药物的药代动力学/药效学结合研究常因其与内源性物质密切的相互作用以及生理调节反馈机制而错综复杂。本文重点阐述了与大多数生物制品相关的一些主要动力学特性及过程,为具有药效特性的多肽和蛋白质疗法提供范例。理解了生物疗法和传统小分子药物之间药动学与药效学的差异,将有助于从事药物研发的科学家以及医疗保健人员在药物开发和应用药物治疗过程中用最适宜的方法去处理、评价和用药。
In recent years, biotechnologically-derived peptides and proteins have developed into mainstream therapeutic agents. Peptide and protein drugs now constitute a substantial portion of the compounds under preclinical and clinical development as well as in clinical practice. The understanding of the phannacokinetics and phannacodynamics, including the dose-concentration-effect relationship, is crucial to any drug-including peptides and proteins-as it lays the foundation for optimal dosing regimen design and rational clinical application. Compared to traditional small molecule-based therapeutics, phannacokinetic and exposure/response evaluations for peptide and protein therapeutics are frequently complicated by their similarity to endogenous peptides and proteins as well as nutrients, by their intimate involvement in physiologic processes on the molecular level, by their macromolecule character and immunogenicity, and by analytical challenges to identify and quantify them in the presence of a myriad of similar molecules. Peptides and proteins, unlike conventional small molecule drugs, are generally not therapeutically active upon oral administration, and selection of the most appropriate route of administration requires comprehensive knowledge of their absorption characteristics beyond physicochemical properties, including chemical and metabolic stability at the absorption site, immunoreactivity, passage through biomembranes, and active uptake and exsorption processes. Various distribution properties dictate whether peptide and protein therapeutics can reach optimum target site exposure in order to exert the intended pharmacological response. Binding phenomena and receptor-mediated cellular uptake may further complicate this issue. Elimination processes-a critical determinant for the drug＇s systemic exposure-may follow a combination of numerous pathways, including renal and hepatic metabolism routes as well as generalized proteolysis and receptor-mediated endocytosis. Phannacokinetic/phannacodynamic （PK/PD） correlations for peptide and protein-based drugs are frequently convoluted by their close interaction with endogenous substances and physiologic regulatory feedback mechanisms. The manuscript highlights some of the major pharmacokinetic properties and processes relevant for the majority of biologics and will provide examples of well characterized phannacodynamic relationships for peptide and protein therapeutics. Appreciation of the pharmacokinetic and phannacodynamic differences between therapeutic biologics and traditional small molecule drugs will empower the drug development scientist as well as the healthcare provider to handle, evaluate and apply these compounds in an optimal fashion during the drug development process as well as in applied pharmacotherapy.
出处
《中国临床药理学与治疗学》
CAS
CSCD
2007年第10期1089-1098,共10页
Chinese Journal of Clinical Pharmacology and Therapeutics
