Xu Yuan, Lee Mark, Joshi Rujuta, Wang Xiaoning, Husband Hillary, Byrne Rena, Waterhouse Tim, Abutarif Malaz, Vaddady Pavan, Garimella Tushar, Li Li
Daiichi Sankyo, Inc., Basking Ridge, New Jersey, USA.
Metrum Research Group, Boston, Massachusetts, USA.
Clin Pharmacokinet. 2025 May 23. doi: 10.1007/s40262-025-01521-4.
Patritumab deruxtecan (HER3-DXd, also known as MK-1022) is an antibody-drug conjugate comprising a fully human monoclonal antibody against human epidermal growth factor receptor 3 (HER3) attached to a topoisomerase I inhibitor payload, deruxtecan (DXd), via a tetrapeptide-based cleavable linker. We developed a population pharmacokinetic (PK) model for anti-HER3-ac-DXd (anti-HER3 antibody conjugated DXd) and DXd to characterize their PKs and investigate the impact of preselected covariates.
Data were pooled from four phase I/II studies including patients with breast, lung, and colorectal cancer (N = 733) treated with HER3-DXd monotherapy (1.6-8.0 mg/kg intravenously every 3 weeks). An integrated population PK model, established using stepwise methodology, simultaneously described both anti-HER3-ac-DXd and DXd disposition.
Anti-HER3-ac-DXd PK was described by a two-compartment model with three elimination pathways: linear transient clearance, nonspecific time-dependent clearance, and nonlinear Michaelis-Menten clearance. DXd PK was described by a one-compartment model with two clearance pathways: linear and nonlinear Michaelis-Menten clearance. The formation of DXd was rate limited by all three clearance pathways of anti-HER3-ac-DXd. Moderate hepatic impairment was a significant covariate on DXd but not anti-HER3-ac-DXd exposure. Other prespecified covariates did not have a clinically important impact on exposure to anti-HER3-ac-DXd or DXd.
The final integrated population PK model characterized the PK of both anti-HER3-ac-DXd and DXd in patients with solid tumors treated with HER3-DXd and supported the selected 5.6 mg/kg Q3W dosing regimen. Consistent with current data, dose adjustment based on the covariates investigated is not warranted.
帕妥珠单抗德卢替康（HER3-DXd，也称为MK-1022）是一种抗体药物偶联物，由一种针对人表皮生长因子受体3（HER3）的全人单克隆抗体通过基于四肽的可裂解连接子与拓扑异构酶I抑制剂有效载荷德卢替康（DXd）连接而成。我们建立了抗HER3-ac-DXd（抗HER3抗体偶联DXd）和DXd的群体药代动力学（PK）模型，以表征它们的药代动力学特征，并研究预先选定的协变量的影响。
数据汇总自四项I/II期研究，包括接受HER3-DXd单药治疗（每3周静脉注射1.6 - 8.0 mg/kg）的乳腺癌、肺癌和结直肠癌患者（N = 733）。使用逐步方法建立的综合群体PK模型同时描述了抗HER3-ac-DXd和DXd的处置过程。
抗HER3-ac-DXd的药代动力学由一个具有三种消除途径的二室模型描述：线性瞬时清除、非特异性时间依赖性清除和非线性米氏清除。DXd的药代动力学由一个具有两种清除途径的一室模型描述：线性和非线性米氏清除。DXd的形成受抗HER3-ac-DXd的所有三种清除途径的速率限制。中度肝功能损害是影响DXd暴露的一个显著协变量，但对抗HER3-ac-DXd暴露无影响。其他预先指定的协变量对抗HER3-ac-DXd或DXd的暴露没有临床重要影响。
最终的综合群体PK模型表征了接受HER3-DXd治疗的实体瘤患者中抗HER3-ac-DXd和DXd的药代动力学特征，并支持选定的5.6 mg/kg每3周一次的给药方案。与当前数据一致，无需根据所研究的协变量进行剂量调整。
