Population pharmacokinetics of trastuzumab in patients With HER2+ metastatic breast cancer
Population pharmacokinetics of trastuzumab in patients With HER2+ metastatic breast cancer
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DOI：
10.1007/s00280-005-1026-z
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发表时间：
2005-10-01
影响因子：
3
通讯作者：
Klein, P
中科院分区：
文献类型：
--
作者：
Bruno, R;Washington, CB;Klein, P
目的：研究曲妥珠单抗在转移性乳腺癌患者中的群体药代动力学特征。方法：非线性混合效应模型基于476例患者的I、II和III期研究的药代动力学数据。I期研究招募了晚期实体瘤患者。II期和III期研究入组了HER 2阳性转移性乳腺癌患者。关键II期和III期研究中的患者接受4 mg/kg负荷剂量的曲妥珠单抗治疗，随后接受2 mg/kg每周一次治疗，持续840天。该模型充分预测了观察到的曲妥珠单抗浓度。模型的稳定性和性能进行了验证，使用自举模拟。百分位数，平均值和标准差的观察水平进行了比较，其分布从100个重复的数据集模拟下的模型。结果如下：二室线性药代动力学模型最好地描述了数据，并解释了曲妥珠单抗每周给药后观察到的长期蓄积。曲妥珠单抗清除率（CL）和中央室分布容积（V-1）基础模型的群体估计值分别为0.225 L/天和2.95 L。基于群体估计值的估计终末半衰期（t（1/2））为28.5天。清除率和容量的患者间变异性分别为43%和29%。转移部位的数量、HER 2受体胞外区的血浆水平和患者体重是清除率、体积或两者的显著基线协变量（P < 0.005）。然而，与CL的较大患者间变异性相比，这些协变量对曲妥珠单抗暴露量的影响是适度的，并且不具有临床意义。伴随化疗（蒽环类药物加环磷酰胺或紫杉醇）似乎不影响清除率。结论：该群体药代动力学模型可以预测转移性乳腺癌患者长期治疗中的曲妥珠单抗暴露量，并通过模拟提供替代剂量方案的比较。
Purpose: To characterize the population pharmacokinetics of trastuzumab in patients with metastatic breast cancer. Methods: A nonlinear mixed effect model was based on pharmacokinetic data from phase I, II, and III studies of 476 patients. The phase I study enrolled patients with advanced solid tumors. The phase II and III studies enrolled patients with HER2-positive metastatic breast cancer. Patients in the pivotal phase II and III studies were treated with a 4 mg/kg loading dose of trastuzumab followed by 2 mg/kg weekly for up to 840 days. The model adequately predicted observed trastuzumab concentrations. Model stability and performance were verified using bootstrap simulations. Percentiles, mean, and standard deviation of observed levels were compared with their distributions from 100 replicates of datasets simulated under the model. Results: A two-compartment linear pharmacokinetic model best described the data and accounted for the long-term accumulation observed following weekly administration of trastuzumab. Population estimates from the base model for clearance (CL) and volume of distribution of the central compartment (V-1) of trastuzumab were 0.225 L/day, and 2.95 L, respectively. Estimated terminal halflife (t(1/2)) based on the population estimate was 28.5 days. Interpatient variabilities in clearance and volume were 43 and 29%, respectively. The number of metastatic sites, plasma level of extracellular domain of the HER2 receptor, and patient weight were significant baseline covariates for clearance, volume, or both (P < 0.005). However, these covariate effects on trastuzumab exposure were modest and not clinically important in comparison with the large inter-patient variability of CL. Concomitant chemotherapy (anthracycline plus cyclophosphamide, or paclitaxel) did not appear to influence clearance. Conclusion: This population pharmacokinetic model can predict trastuzumab exposure in the long-term treatment of patients with metastatic breast cancer and provide comparison of alternative dosage regimens via simulation.