Population pharmacokinetics of cisplatin in adult cancer patients
Population pharmacokinetics of cisplatin in adult cancer patients
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DOI：
10.1007/s00280-004-0790-5
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发表时间：
2004-08-01
影响因子：
3
通讯作者：
Sparreboom, A
中科院分区：
文献类型：
--
作者：
de Jongh, FE;Gallo, JM;Sparreboom, A
目的。表征抗癌药物顺铂的药代动力学，并探讨患者协变量和场合间变异对药物处置的影响。方法。数据来自 285 名患者（519 条完整曲线；3483 个血浆样本），这些患者以 144 mg（范围 75-210 mg）的平均剂量接受 3 小时静脉输注药物。使用NONMEM建立群体模型，进行广义加性建模来识别候选协变量，包括体表面积（BSA）、年龄、性别、身高、体重、血细胞比容、总蛋白、白蛋白、血清肌酐和肌酐清除率，并使用向后删除协议获得清除率（CL）和分布体积（V）的最终模型。结果。最终模型是单室线性模型，其中 BSA（以米为单位）作为影响 CL 和 V 的唯一显着协变量：TVCL（以升/小时为单位）=51.7+26.3x(BSA-1.855) 和 TVV（以升为单位）=41.1+24.6x(BSA-1.855)，其中 TVCL 和 TVV 被称为可以在剂量中先验使用的典型值方案设计。 CL 和 V 的个体间和场合变异性估计值分别为 16.82 和 20.35%、13.93 和 22.91%。结论。已经开发了顺铂的群体药代动力学模型，该模型结合了体型大小的测量来预测清除率。在该患者群体中，顺铂药代动力学与年龄、性别或肾功能障碍指标无关。
Purpose. To characterize the pharmacokinetics of the anticancer agent cisplatin, and explore the influence of patient covariates and interoccasion variability on drug disposition. Methods. Data were obtained from 285 patients (519 complete curves; 3483 plasma samples) who received the drug as a 3-h intravenous infusion at a mean dose of 144 mg (range 75-210 mg). The population model was built with the use of NONMEM, performing generalized-additive modeling to identify candidate covariates including body-surface area (BSA), age, sex, height, weight, hematocrit, total protein, albumin, serum creatinine, and creatinine clearance, and using a backward deletion protocol to obtain the final models for clearance (CL) and volume of distribution (V). Results. The final model was a one-compartment linear model with BSA (in meters squared) as the only significant covariate that impacted on both CL and V: TVCL (in liters per hour)=51.7+26.3x(BSA-1.855) and TVV (in liters)=41.1+24.6x(BSA-1.855), where TVCL and TVV are referred to as typical values that could be used a priori in dosage regimen design. The interindividual and interoccasion variability estimates for CL and V were 16.82 and 20.35%, and 13.93 and 22.91%, respectively. Conclusion. A population pharmacokinetic model for cisplatin has been developed that incorporates measures of body size to predict clearance. In this patient population, cisplatin pharmacokinetics were not associated with age, sex, or measures of renal dysfunction.