Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Route 206 & Province Line Rd., Princeton NJ, 08543, USA; Clinical Pharmacology and Pharmacometrics, 3401 Princeton Pike, Lawrenceville NJ, 08648, USA.
Department of Discovery Synthesis, Small Molecule Drug Discovery, Bristol-Myers Squibb, Route 206 & Province Line Rd., Princeton NJ, 08543, USA.
Eur J Pharm Sci. 2021 Oct 1;165:105928. doi: 10.1016/j.ejps.2021.105928. Epub 2021 Jul 12.
Conjugation with polyethylene glycol (PEG), PEGylation, has been considered a useful tool to improve drug-like properties of novel small molecules and biologics in drug discovery. PEG40 or 40 kDa PEG is a double-branched PEG, routinely employed to improve the pharmacokinetics (PK) of therapeutics, including successful marketed products such as Pegasys® and Omontys®. However, less is known about the extent of contribution of PEG40 to the overall PK of the PEGylated product. Considering the half-life of PEG40 conjugated PEGylated products ranges from 1 to 14 days in human, this information is immensely valuable. After successfully developing a high sensitivity NMR based analytical method to quantitate PEG40 in mice serum after intravenous (IV) administration (Khandelwal et al., 2019), here, we extend its application to measure PEG40 in serum after IV administration and subcutaneous (SC) absorption in routinely employed non-clinical species in drug discovery, namely, mice, rats and cynomolgus monkeys. We utilized non-compartmental analysis and compartmental modeling to characterize the PK of PEG40 in these non-clinical species. Finally, we employed allometric scaling and Wajima (MRT-Css) method to predict the PK of PEG40 in human after IV administration and SC absorption. In general, our data shows that intrinsic PK parameters of PEG40 in mice, rats and cynomolgus monkeys are in the range of published literature values for PEG40-conjugated products, unless saturable clearance mechanisms are involved. We observed a bioavailability (F) of ~68% in CD-1 mice after SC administration of PEG40. In rats, the clearance (CL) and volume of distribution at steady state (V) after IV infusion of PEG40 were 0.079 mL/min/kg and 0.19 L/kg, respectively; and SC bioavailability was ~20%. In cynomolgus monkeys, after IV infusion, CL and V of PEG40 were 0.037 mL/min/kg and 0.20 L/kg, respectively; and SC bioavailability was ~69%. In addition, our findings indicate flip-flop kinetics of PEG40 in rodents, but not in cynomolgus monkeys. Finally, in human, intrinsic CL and V of PEG40 were projected to be 0.02 mL/min/kg (0.084 L/h) and 0.22 L/kg, respectively. This comprehensive report of PK of PEG40 in non-clinical species and its subsequent prediction in humans is expected to be useful to drug discovery and development scientists for efficient decision-making and optimal resource utilization.
聚乙二醇（PEG）缀合，即 PEG 化，已被认为是改善新药小分子和生物制剂药物特性的有用工具。PEG40 或 40 kDa PEG 是一种双分支 PEG，常用于改善治疗药物的药代动力学（PK），包括 Pegasys®和 Omontys®等成功上市的产品。然而，对于 PEG40 对 PEG 化产品总体 PK 的贡献程度知之甚少。鉴于 PEG40 缀合的 PEG 化产品在人体内的半衰期范围为 1 至 14 天，这些信息非常有价值。在成功开发了一种基于高灵敏度 NMR 的分析方法来定量检测静脉注射（IV）后小鼠血清中的 PEG40（Khandelwal 等人，2019）后，我们将其应用扩展到测量 IV 给药后和常规用于药物发现的非临床物种（即小鼠、大鼠和食蟹猴）中皮下（SC）吸收后血清中的 PEG40。我们利用非房室分析和房室建模来描述这些非临床物种中 PEG40 的 PK。最后，我们采用比例缩放和 Wajima（MRT-Css）法来预测 IV 给药和 SC 吸收后人类 PEG40 的 PK。一般来说，我们的数据表明，除非涉及饱和清除机制，否则 PEG40 在小鼠、大鼠和食蟹猴中的固有 PK 参数在已发表的 PEG40 缀合产品文献值范围内。我们观察到 CD-1 小鼠经 SC 给予 PEG40 的生物利用度（F）约为 68%。在大鼠中，PEG40 静脉输注后清除率（CL）和稳态时分布容积（V）分别为 0.079 mL/min/kg 和 0.19 L/kg；SC 生物利用度约为 20%。在食蟹猴中，静脉输注后 PEG40 的 CL 和 V 分别为 0.037 mL/min/kg 和 0.20 L/kg；SC 生物利用度约为 69%。此外，我们的研究结果表明 PEG40 在啮齿动物中存在翻转动力学，但在食蟹猴中不存在。最后，在人体内，PEG40 的固有 CL 和 V 预计分别为 0.02 mL/min/kg（0.084 L/h）和 0.22 L/kg。本报告全面描述了非临床物种中 PEG40 的 PK，并随后预测了其在人类中的 PK，预计这将对药物发现和开发科学家有用，有助于他们做出高效决策和优化资源利用。
