Nagai N, Ogata H, Wada Y, Tsujino D, Someya K, Ohno T, Masuhara K, Tanaka Y, Takahashi H, Nagai H, Kato K, Koshiba Y, Igarashi T, Yokoyama A, Kinameri K, Kato T, Kurita Y
Department of Biopharmaceutics, Meiji Pharmaceutical University, Tokyo, Japan.
J Clin Pharmacol. 1998 Nov;38(11):1025-34. doi: 10.1177/009127009803801107.
The population pharmacokinetics and pharmacodynamics of cisplatin (CDDP) were evaluated based on a mixed-effect model using the NONMEM program. Unchanged CDDP in plasma was measured as a biologically active platinum species during CDDP chemotherapy, using high-performance liquid chromatography. Plasma concentration measurements (157) of unchanged CDDP from 26 patients with cancer receiving 80 mg/m2 CDDP by infusion over 2 hours, 3.5 hours, or 4 hours were analyzed according to a one-compartment model. The influences of individual characteristics such as body weight, dose schedule, course, and clinical laboratory values (renal function markers, albumin) on total body clearance (Cl) and volume of distribution (Vd) were examined. In the final pharmacokinetic model, body surface area and dose schedule affected Cl of unchanged CDDP. The Cl of CDDP was increased by 27.3% after the 2-hour infusion schedule compared with Cl after the longer infusions. The Vd was estimated as 13.4 L/m2. The interindividual variability for Cl and Vd and residual variability were 22.9%, 30.9%, and 35.5%, respectively. The relationships between maximum concentration (Cmax) of unchanged CDDP and maximum blood urea nitrogen (BUNmax), or minimum creatinine clearance (ClCr,min) over a 1-month period after CDDP administration were evaluated according to linear, exponential, or maximum response (Emax) models. The linear or Emax model described pharmacodynamics most successfully, with relatively large interindividual variability for both slope and EC50 (more than 25%). Residual variability was 15.3% and 17.1% in BUNmax and Clcrmin, respectively. The population means and interindividual and residual variability of pharmacokinetics and pharmacodynamics of CDDP were evaluated using the NONMEM program. The results of this study show that the population pharmacokinetic and pharmacodynamic approach could be useful to manage CDDP nephrotoxicity using sparse data in a clinical setting.
基于混合效应模型，使用NONMEM程序评估顺铂（CDDP）的群体药代动力学和药效学。在CDDP化疗期间，采用高效液相色谱法将血浆中未变化的CDDP作为生物活性铂物种进行测量。对26例接受80mg/m² CDDP静脉输注2小时、3.5小时或4小时的癌症患者的未变化CDDP的血浆浓度测量值（157个），根据一室模型进行分析。研究了个体特征（如体重、给药方案、疗程和临床实验室值（肾功能标志物、白蛋白））对总体清除率（Cl）和分布容积（Vd）的影响。在最终的药代动力学模型中，体表面积和给药方案影响未变化CDDP的Cl。与较长输注时间后的Cl相比，2小时输注方案后CDDP的Cl增加了27.3%。Vd估计为13.4L/m²。Cl和Vd的个体间变异性以及残差变异性分别为22.9%、30.9%和35.5%。根据线性、指数或最大反应（Emax）模型评估CDDP给药后1个月内未变化CDDP的最大浓度（Cmax）与最大血尿素氮（BUNmax）或最小肌酐清除率（ClCr,min）之间的关系。线性或Emax模型最成功地描述了药效学，斜率和EC50的个体间变异性相对较大（超过25%）。BUNmax和Clcrmin的残差变异性分别为15.3%和17.1%。使用NONMEM程序评估CDDP药代动力学和药效学的群体均值、个体间和残差变异性。本研究结果表明，群体药代动力学和药效学方法可用于在临床环境中使用稀疏数据管理CDDP肾毒性。
