Population pharmacokinetics of cabazitaxel in patients with advanced solid tumors
Population pharmacokinetics of cabazitaxel in patients with advanced solid tumors
复制标题
DOI：
10.1007/s00280-012-2058-9
复制
发表时间：
2013-03-01
影响因子：
3
通讯作者：
Semiond, Dorothee
中科院分区：
文献类型：
--
作者：
Ferron, Geraldine M.;Dai, Yang;Semiond, Dorothee
为了建立卡巴他赛在晚期实体瘤患者中的群体药代动力学（PK）模型，并检测人口统计学和基线参数的影响，我们对5项I-III期研究中每7天或21天接受卡巴他赛（10 - 30 mg/m2，1小时IV输注）的170例患者进行了非线性混合效应模型（NONMEM VI）分析。模型评价包括非参数bootstrap和直观预测检查。卡巴他赛PK最好用线性三室模型描述：一级消除;清除率（CL）、中心分布容积（V1）和除K21外的所有房室间速率常数的个体间变异性; CL和V1的病例间变异性;比例残差为27.8%。卡巴他赛CL与体表面积（BSA）和肿瘤类型（乳腺癌;研究结果混淆）相关。BSA为1.84 m2的非乳腺癌患者的典型CL为48.5 L/h，V1为26.0 L，稳态分布容积为4，870 L，α、β和γ半衰期分别为4.4 min、1.6和95 h。性别、身高、体重、年龄、高加索人种、肾/肝功能和细胞色素P450诱导剂的使用未显著进一步解释卡巴他赛的PK。Bootstrap和后验预测检验证实了该模型的充分性。卡巴他赛PK似乎不受大多数基线患者因素的影响，BSA对CL的影响实际上通过BSA依赖性剂量来解决。该分析表明，大多数实体瘤类型的卡巴他赛PK和暴露量一致，尽管乳腺癌对CL的潜在影响需要进一步确认。
To develop a population pharmacokinetic (PK) model for cabazitaxel in patients with advanced solid tumors and examine the influence of demographic and baseline parameters.One hundred and seventy patients who received cabazitaxel (10-30 mg/m(2), 1-h IV infusion) every 7 or 21 days in five Phase I-III studies were analyzed by non-linear mixed-effect modeling (NONMEM VI). Model evaluation comprised non-parametric bootstrap and visual predictive checks.Cabazitaxel PK was best described by a linear three-compartment model with: first-order elimination; interindividual variability on clearance (CL), central volume of distribution (V1), and all intercompartmental rate constants except K21; interoccasion variability in CL and V1; proportional residual error of 27.8 %. Cabazitaxel CL was related to body surface area (BSA) and tumor type (breast cancer; finding confounded by study). Typical CL for a non-breast cancer patient with a BSA of 1.84 m(2) was 48.5 L/h, with V1 26.0 L, steady-state volume of distribution 4,870 L and alpha, beta, and gamma half-lives of 4.4 min, 1.6, and 95 h, respectively. Sex, height, weight, age, Caucasian race, renal/hepatic function, and cytochrome P450 inducer use did not significantly further explain the PK of cabazitaxel. Bootstrap and posterior predictive checks confirmed the adequacy of the model.Cabazitaxel PK appears unaffected by most baseline patient factors, and the influence of BSA on CL is addressed in practice by BSA-dependent doses. This analysis suggests consistent cabazitaxel PK and exposure across most solid tumor types, although the potential influence of breast cancer on CL requires further confirmation.