Genentech, Inc., 1 DNA Way, Mail Stop 463A, South San Francisco, CA, 94080, USA.
Certara, L.P., 845 Oak Grove Ave, Menlo Park, CA, 94025, USA.
Cancer Chemother Pharmacol. 2019 Feb;83(2):329-340. doi: 10.1007/s00280-018-3728-z. Epub 2018 Nov 22.
The aim of the study was to characterize the population pharmacokinetics (PK) of the intravenous formulation of trastuzumab, assess the impact of patient and pathological covariates on trastuzumab PK, and perform simulations to support dosing recommendations in special situations.
Serum trastuzumab concentrations were obtained from 1582 patients with metastatic breast cancer (MBC), early breast cancer (EBC), advanced gastric cancer (AGC), or other tumor types/healthy volunteers in 18 phase I, II, and III trials and analyzed by nonlinear mixed-effects modeling.
A two-compartment model with parallel linear and nonlinear elimination best described the data. During treatment, linear clearance (CL) dominated, resulting in a total CL of 0.173-0.337 L/day, which is similar to other IgG1 monoclonal antibodies. Covariates influencing CL were baseline body weight, aspartate aminotransferase, albumin, gastric cancer, and the presence of liver metastases. MBC and EBC had similar PK parameters, while CL was higher in AGC. Simulations indicated that at least 95% of patients with BC reach concentrations < 1 µg/mL (~ 97% washout) by 7 months. A dose delay in BC or AGC patients of > 1 week would take approximately 6 weeks to get back within steady-state exposure range.
Trastuzumab PK for the intravenous formulation was well-described across cancer types, disease status, and regimens. No dose adjustment is required for any of the identified patient covariates. A 7-month serum washout period for trastuzumab is recommended. A reloading dose is required if a maintenance dose is missed by > 1 week.
本研究旨在描述曲妥珠单抗静脉制剂的群体药代动力学（PK），评估患者和病理因素对曲妥珠单抗 PK 的影响，并进行模拟以支持特殊情况下的给药建议。
从 18 项 I、II 和 III 期临床试验中，1582 例转移性乳腺癌（MBC）、早期乳腺癌（EBC）、晚期胃癌（AGC）或其他肿瘤类型/健康志愿者的血清曲妥珠单抗浓度中获得数据，并通过非线性混合效应模型进行分析。
两室模型加平行线性和非线性消除能够最好地描述数据。在治疗期间，线性清除率（CL）占主导地位，导致总 CL 为 0.173-0.337 L/天，与其他 IgG1 单克隆抗体相似。影响 CL 的协变量包括基线体重、天冬氨酸转氨酶、白蛋白、胃癌和肝转移的存在。MBC 和 EBC 的 PK 参数相似，而 AGC 的 CL 较高。模拟表明，至少 95%的 BC 患者在 7 个月内达到浓度<1μg/mL（~97%清除）。BC 或 AGC 患者的剂量延迟>1 周，大约需要 6 周才能恢复到稳态暴露范围内。
曲妥珠单抗静脉制剂的 PK 在各种癌症类型、疾病状态和治疗方案中均得到了很好的描述。对于任何确定的患者协变量，都不需要调整剂量。建议曲妥珠单抗的血清清除期为 7 个月。如果错过维持剂量>1 周，则需要重新加载剂量。
