Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.
Eur J Drug Metab Pharmacokinet. 2023 Sep;48(5):541-552. doi: 10.1007/s13318-023-00845-5. Epub 2023 Aug 2.
Fc fusion is an effective strategy for extending the half-lives of therapeutic proteins. This study aimed to evaluate the applicability of a human pharmacokinetics prediction method for Fc-fusion proteins by extending on reported methods for monoclonal antibodies (mAbs).
To predict human pharmacokinetic profiles following intravenous (IV) dosing, the pharmacokinetic data for 11 Fc-fusion proteins in monkeys were analysed by two approaches: a species-invariant time method with a range of allometric exponents in clearance (CL, 0.7-1.0) and a two-compartment model reported for mAbs. The pharmacokinetic profiles following subcutaneous (SC) dosing were predicted by simple dose normalisation from monkeys or using the geometric means of the absorption rate constant (Ka) and bioavailability (BA) for mAbs or Fc-fusion proteins in humans and compared.
In the case of IV administration, the area under the curve could be predicted for more than 85% of Fc-fusion proteins within a twofold difference from the observed value using the species-invariant time method (scaling exponent for CL, 0.95). For SC dosing, incorporating the geometric means of absorption parameters for both mAbs (BA 68.2%, Ka 0.287 day) and Fc-fusion proteins (BA 63.0%, Ka 0.209 day) in humans provided better accuracy than simple normalisation from monkeys.
We have successfully predicted the human pharmacokinetic profiles of Fc-fusion proteins for both IV and SC administration within twofold of the observed value from monkey pharmacokinetic data by extending on reported methods for mAbs. This method will facilitate drug discovery and development of Fc-fusion proteins.
Fc 融合是延长治疗性蛋白半衰期的有效策略。本研究旨在通过扩展单克隆抗体（mAb）的报告方法，评估用于 Fc 融合蛋白的人体药代动力学预测方法的适用性。
为了预测静脉内（IV）给药后人体药代动力学特征，通过两种方法分析了 11 种 Fc 融合蛋白在猴子中的药代动力学数据：一种是具有清除率（CL，0.7-1.0）范围内各种变异性指数的物种不变时间法，另一种是针对 mAb 报告的两室模型。通过简单地从猴子中进行剂量归一化，或使用 mAb 或 Fc 融合蛋白在人体中的吸收速率常数（Ka）和生物利用度（BA）的几何平均值来预测皮下（SC）给药后的药代动力学特征，并进行比较。
在 IV 给药的情况下，使用物种不变时间法（CL 的比例指数为 0.95），可以预测超过 85%的 Fc 融合蛋白的 AUC，其预测值与观察值的差异在两倍以内。对于 SC 给药，在人体中纳入 mAb（BA 68.2%，Ka 0.287 天）和 Fc 融合蛋白（BA 63.0%，Ka 0.209 天）吸收参数的几何平均值比简单地从猴子中进行归一化提供了更好的准确性。
通过扩展针对 mAb 的报告方法，我们成功地预测了 Fc 融合蛋白在猴子的药代动力学数据范围内，IV 和 SC 给药后人体药代动力学特征，其预测值与观察值的差异在两倍以内。该方法将促进 Fc 融合蛋白的药物发现和开发。
