Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas 66047; Department of Pharmacokinetics, Pharmacodynamics & Drug Metabolism (PPDM), Merck Research Laboratories, West Point, Pennsylvania 19486.
Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas 66047; MedImmune, Gaithersburg, Maryland 20878.
J Pharm Sci. 2020 Jan;109(1):191-205. doi: 10.1016/j.xphs.2019.08.005. Epub 2019 Aug 10.
The intradermal (ID) and subcutaneous (SC) routes are commonly used for therapeutic proteins (TPs) and vaccines; however, the bioavailability of TPs is typically less than small molecule drugs given via the same routes. Proteolytic enzymes in the dermal, SC, and lymphatic tissues may be responsible for the loss of TPs. In addition, the TPs may be exposed to reactive oxygen species generated in the SC tissue and the lymphatic system in response to injection-related trauma and impurities within the formulation. The reactive oxygen species can oxidize TPs to alter their efficacy and immunogenicity potential. Mechanistic understandings of the dominant proteolysis and oxidative routes are useful in the drug discovery process, formulation development, and to assess the potential for immunogenicity and altered pharmacokinetics (PK). Furthermore, in vitro tools representing the ID or SC and lymphatic system can be used to evaluate the extent of proteolysis of the TPs after the injection and before systemic entry. The in vitro clearance data may be included in physiologically based pharmacokinetic models for improved PK predictions. In this review, we have summarized various physiological factors responsible for proteolysis and oxidation of TPs after ID and SC administration.
皮内（ID）和皮下（SC）途径通常用于治疗性蛋白质（TPs）和疫苗；然而，通过相同途径给予的 TPs 的生物利用度通常低于小分子药物。真皮、SC 和淋巴组织中的蛋白水解酶可能是导致 TPs 损失的原因。此外，TPs 可能会暴露于 SC 组织和淋巴系统中因注射相关创伤和制剂内杂质而产生的活性氧物质。活性氧物质可以氧化 TPs，从而改变其疗效和免疫原性潜力。对主要蛋白水解和氧化途径的机制理解有助于药物发现过程、制剂开发以及评估免疫原性和改变药代动力学（PK）的潜力。此外，代表 ID 或 SC 和淋巴系统的体外工具可用于评估注射后进入全身循环前 TPs 的蛋白水解程度。体外清除数据可包含在基于生理学的药代动力学模型中，以提高 PK 预测。在这篇综述中，我们总结了各种生理因素，这些因素负责 TPs 在 ID 和 SC 给药后的蛋白水解和氧化。
