Biostatistical Modeling for Pharmacokinetics and Pharmacodynamics of Anticancer Agents and Application to Individualized Dosage Regimen

多西他赛（taxoere）的药代动力学和药效学研究是通过对102名参加I期和II期临床试验的日本患者的662个血浆浓度数据进行人群分析进行的。多西他赛在10- 90mg /m^2剂量范围内的分布用3室线性模型描述。NONMEN分析显示，多西他赛清除率与体表面积（BSA,m^2）和血清白蛋白水平（ALB,g/100ml）相关，与α _1-酸性糖蛋白水平（AAG,mg/100ml）和年龄呈负相关。以GOT或GPT升高大于60 IU/L为指标的肝功能不全（HEP1=1）患者清除率降低12%。总体平均清除率为：CL=BSA (37.0-0.0629AAG-0.192AGE+0.542ALB) （1-0.124HEP1）。剩余的个体间变异率为26%。这些结果与在欧洲和美国人群中获得的结果相当，表明在多西他赛的消除方面没有种族差异。采用乙状结肠Emax模型描述药代动力学特征与剂量限制性毒性（骨髓抑制）之间的关系。浓度-时间曲线下面积（AUC）是骨髓抑制严重程度的决定因素。然而，疗效与AUC值无关。本研究结果对优化多西他赛剂量有一定的指导意义。

Pharmacokinetics and pharmacodynamics of docetaxl (Taxotere) have been investigated by a population analysis using the 662 plasma concentration data obtained from 102 Japanese patients who participated in the phase I and II clinical trials. Docetaxl disposition was described by a 3-compartment linear model at the dose range of 10-90 mg/m^2. NONMEN analysis showed that the docetaxl clearance was related to the body surface area (BSA,m^2) and serum albumin level (ALB,g/100ml) and inversely correlated with alpha_1-acid glycoprotein level (AAG,mg/100ml) and age. The patients having hepatic dysfunction (HEP1=1) indicated by the elevation of GOT or GPT greater than 60 IU/L showed 12% reduction in clearance. The population mean of clearance was described by the equation : CL=BSA (37.0-0.0629AAG-0.192AGE+0.542ALB) (1-0.124HEP1). The remaining interindividual variability was 26%. These results were comparable to those obtained in European and American population, suggesting no racial difference in the elimination of docetaxl. The relationships between pharmacokinetic characteristics and the dose limiting toxicity (myelosuppression) were described by a sigmoid Emax model. The area under the concentration-time curve (AUC) was a determining factor for the severity of myelosuppression. However, the efficacy was not correlated with the AUC values. The present findings are useful for optimizing docetaxl dosage.