Quantitative Clinical Pharmacology and Translational Sciences, Daiichi Sankyo, Inc, Basking Ridge, New Jersey, USA.
Certara Strategic Consulting, Princeton, New Jersey, USA.
Clin Pharmacol Ther. 2021 May;109(5):1314-1325. doi: 10.1002/cpt.2096. Epub 2020 Dec 6.
Trastuzumab deruxtecan (DS-8201) is a human epidermal growth factor receptor 2 (HER2)-targeting antibody-drug conjugate with a novel enzyme-cleavable linker, a topoisomerase I inhibitor payload, and a drug-to-antibody ratio of ≈ 8. We have characterized the population pharmacokinetics (PK) of trastuzumab deruxtecan and released drug (topoisomerase I inhibitor) in patients with HER2-positive breast cancer or other solid tumor malignancies. This analysis includes pooled data from five clinical studies with 639 patients. Trastuzumab deruxtecan doses ranged from 0.8 to 8.0 mg/kg every 3 weeks. Serum concentrations of trastuzumab deruxtecan and released drug were analyzed using a sequential two-step approach, with the nonlinear mixed-effects modeling methods. Covariate assessment was based upon stepwise forward-addition and backward-elimination process, followed by both univariate and multivariate analysis quantifying their impact on steady-state exposure of trastuzumab deruxtecan and released drug. A two-compartment model with linear elimination best described PK profiles of intact trastuzumab deruxtecan, while a one-compartment model with time-varying release-rate constant and linear elimination described released-drug PK profiles. Statistically significant covariates (country, tumor size, sex, formulation, age, body weight, albumin, total bilirubin, and aspartate aminotransferase) resulted in < 20% change in steady-state area under the concentration-time curve of trastuzumab deruxtecan and released drug, except for increased body weight (95th percentile, 86 kg) and decreased albumin (5th percentile, 31 g/L). Analysis of patients stratified by country, race, renal function, and hepatic function found no clinically meaningful differences in steady-state exposure of intact trastuzumab deruxtecan or released drug. Overall, results suggest that no dose adjustment based on tested covariates or in specific patient populations is warranted.
曲妥珠单抗-美坦新偶联物（DS-8201）是一种人表皮生长因子受体 2（HER2）靶向抗体-药物偶联物，具有新型酶切连接子、拓扑异构酶 I 抑制剂有效载荷和约 8 的药物抗体比。我们已经对曲妥珠单抗-美坦新偶联物及其释放药物（拓扑异构酶 I 抑制剂）在 HER2 阳性乳腺癌或其他实体瘤恶性肿瘤患者中的群体药代动力学（PK）进行了特征描述。该分析包括来自五项临床试验的 639 例患者的汇总数据。曲妥珠单抗-美坦新偶联物的剂量范围为 0.8 至 8.0mg/kg，每 3 周一次。采用两步序贯方法，通过非线性混合效应模型方法分析曲妥珠单抗-美坦新偶联物和释放药物的血清浓度。基于逐步正向添加和反向消除过程进行协变量评估，然后进行单变量和多变量分析，以量化其对曲妥珠单抗-美坦新偶联物和释放药物稳态暴露的影响。完整的曲妥珠单抗-美坦新偶联物的 PK 曲线最好用具有线性消除的两室模型描述，而释放药物的 PK 曲线则用具有时变释放速率常数和线性消除的一室模型描述。具有统计学意义的协变量（国家、肿瘤大小、性别、剂型、年龄、体重、白蛋白、总胆红素和天冬氨酸氨基转移酶）导致曲妥珠单抗-美坦新偶联物和释放药物的稳态 AUC 变化小于 20%，除了体重增加（第 95 百分位数，86kg）和白蛋白减少（第 5 百分位数，31g/L）。按国家、种族、肾功能和肝功能分层的患者分析未发现完整的曲妥珠单抗-美坦新偶联物或释放药物稳态暴露的临床相关差异。总体而言，结果表明，无需根据测试协变量或特定患者人群进行剂量调整。
