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

使用从参加I期和II期临床试验的102例日本患者中获得的662个血浆浓度数据，通过人群分析研究了紫杉醇（泰索帝）的药代动力学和药效学。在10-90 mg/m^2剂量范围内，多西他赛的分布通过三室线性模型描述。NONMEN分析表明，紫杉醇清除率与体表面积（BSA，m^2）、血清白蛋白（ALB，g/100 ml）有关，与α_1-酸性糖蛋白（AAG，mg/100 ml）、年龄呈负相关。GOT或GPT升高大于60 IU/L表明肝功能障碍（HEP 1 =1）的患者显示清除率降低12%。清除率的群体平均值由以下方程描述：CL=BSA（37.0-0.0629AAG-0.192AGE+0.542ALB）（1-0.124HEP1）。其余个体间变异性为26%。这些结果与在欧洲和美国人群中获得的结果相当，表明在紫杉醇消除方面没有种族差异。采用S形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值不相关。本研究结果可为紫杉醇的剂量优化提供参考。

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.