Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Avenue, Rm. 444, Memphis, TN, 38163, USA.
Clin Pharmacokinet. 2013 Oct;52(10):855-68. doi: 10.1007/s40262-013-0079-0.
Peptides, defined as polymers of less than 50 amino acids with a molecular weight of less than 10 kDa, represent a fast-growing class of new therapeutics which has unique pharmacokinetic characteristics compared to large proteins or small molecule drugs. Unmodified peptides usually undergo extensive proteolytic cleavage, resulting in short plasma half-lives. As a result of their low permeability and susceptibility to catabolic degradation, therapeutic peptides usually have very limited oral bioavailability and are administered either by the intravenous, subcutaneous, or intramuscular route, although other routes such as nasal delivery are utilized as well. Distribution processes are mainly driven by a combination of diffusion and to a lesser degree convective extravasation dependent on the size of the peptide, with volumes of distribution frequently not larger than the volume of the extracellular body fluid. Owing to the ubiquitous availability of proteases and peptidases throughout the body, proteolytic degradation is not limited to classic elimination organs. Since peptides are generally freely filtered by the kidneys, glomerular filtration and subsequent renal metabolism by proteolysis contribute to the elimination of many therapeutic peptides. Although small peptides have usually limited immunogenicity, formation of anti-drug antibodies with subsequent hypersensitivity reactions has been described for some peptide therapeutics. Numerous strategies have been applied to improve the pharmacokinetic properties of therapeutic peptides, especially to overcome their metabolic instability, low permeability, and limited tissue residence time. Applied techniques include amino acid substitutions, modification of the peptide terminus, inclusion of disulfide bonds, and conjugation with polymers or macromolecules such as antibody fragments or albumin. Application of model-based pharmacokinetic-pharmacodynamic correlations has been widely used for therapeutic peptides in support of drug development and dosage regimen design, especially because their targets are often well-described endogenous regulatory pathways and processes.
肽是指由少于 50 个氨基酸组成、分子量小于 10 kDa 的聚合物，与大蛋白或小分子药物相比，它们代表了一类快速发展的新型治疗药物，具有独特的药代动力学特征。未经修饰的肽通常会经历广泛的蛋白水解切割，导致其血浆半衰期较短。由于其低通透性和易被代谢降解，治疗性肽通常具有非常有限的口服生物利用度，只能通过静脉、皮下或肌肉途径给药，尽管也会采用其他途径，如鼻内给药。分布过程主要由扩散和较小程度的对流渗出驱动，这取决于肽的大小，其分布容积通常不大于细胞外体液的容积。由于蛋白酶和肽酶在全身普遍存在，蛋白水解降解不仅限于经典的消除器官。由于肽通常可被肾脏自由滤过，肾小球滤过和随后的肾内代谢通过蛋白水解作用有助于许多治疗性肽的消除。虽然小肽通常具有有限的免疫原性，但已描述了一些肽治疗剂形成抗药物抗体和随后的过敏反应。已经应用了许多策略来改善治疗性肽的药代动力学特性，特别是克服其代谢不稳定性、低通透性和有限的组织停留时间。应用的技术包括氨基酸取代、肽末端修饰、包含二硫键以及与聚合物或大分子（如抗体片段或白蛋白）缀合。模型为基础的药代动力学-药效动力学相关性的应用已广泛用于治疗性肽，以支持药物开发和剂量方案设计，尤其是因为它们的靶标通常是描述良好的内源性调节途径和过程。
