Daiichi Sankyo, Inc., Basking Ridge, New Jersey, USA.
Daiichi Sankyo Co., Ltd, Tokyo, Japan.
J Clin Pharmacol. 2023 Jan;63(1):77-90. doi: 10.1002/jcph.2137. Epub 2022 Sep 17.
Patritumab deruxtecan is an antibody-drug conjugate consisting of a fully human monoclonal antibody against human epidermal growth factor receptor 3 (HER3) attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. As part of the pharmacometric analysis informing dose selection for later-stage development, population pharmacokinetics (PK) analysis of patritumab deruxtecan was conducted with pooled serum PK data from patients with HER3-expressing solid tumors (from 3 phase 1/2 studies in breast, lung, and colorectal cancer; N = 425) treated over the dose range of 1.6 to 8.0 mg/kg intravenously every 3 weeks. Population PK modeling for deruxtecan (DXd)-conjugated antibody (representing patritumab deruxtecan) and unconjugated MAAA-1181a (DXd, payload) was carried out sequentially. DXd-conjugated antibody PK was described using a 2-compartment model with parallel linear and nonlinear clearance. Unconjugated DXd PK was described using a 1-compartment model with linear clearance and release of DXd as a first-order, time-dependent function of the level of DXd-conjugated antibody in the central compartment. Preliminary covariate evaluation was conducted for prespecified covariates of pharmacological plausibility and clinical interest. The final model retained weight (on linear clearance and central volume) and albumin level, sex, and tumor type (on linear clearance) for DXd-conjugated antibody, and weight (on release rate constant) and hepatic function (on clearance) for unconjugated DXd. Effects of these covariates on the exposure metrics were generally mild and did not require dose adjustment for subpopulations in subsequent development. Further PK characterization for patritumab deruxtecan will evolve with emerging data.
帕妥珠单抗 deruxtecan 是一种抗体药物偶联物，由一个完全人源化单克隆抗体组成，该抗体针对人类表皮生长因子受体 3（HER3），通过一个四肽连接子与拓扑异构酶 I 抑制剂有效载荷相连。作为为后期开发确定剂量的药效学分析的一部分，对帕妥珠单抗 deruxtecan 的群体药代动力学（PK）进行了分析，纳入了来自表达 HER3 的实体瘤患者（来自 3 项乳腺癌、肺癌和结直肠癌的 1/2 期研究；N=425）的血清 PK 数据，这些患者接受了 1.6 至 8.0mg/kg 的剂量范围，每 3 周静脉给药一次。先后进行了代表帕妥珠单抗 deruxtecan 的 deruxtecan（DXd）-缀合抗体和未缀合的 MAAA-1181a（DXd，有效载荷）的群体 PK 建模。DXd-缀合抗体 PK 使用具有平行线性和非线性清除的 2 隔室模型进行描述。未缀合的 DXd PK 使用 1 隔室模型进行描述，其中线性清除和 DXd 的释放是中央隔室中 DXd-缀合抗体水平的一阶、时变函数。对具有药理学合理性和临床意义的预设协变量进行了初步协变量评估。最终模型保留了权重（线性清除和中央容积）和白蛋白水平、性别和肿瘤类型（线性清除），用于 DXd-缀合抗体，以及体重（释放速率常数）和肝功能（清除），用于未缀合的 DXd。这些协变量对暴露指标的影响通常较轻，不需要在后续开发中为亚人群调整剂量。随着新数据的出现，对帕妥珠单抗 deruxtecan 的进一步 PK 特征描述将不断发展。
