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

多西他赛(泰索帝)的药代动力学和药效学研究采用总体分析方法，使用参加I期和II期临床试验的102名日本患者的662个血药浓度数据。多西他赛在10-90 mg/m~2剂量范围内的吸收符合三室线性模型。NONMEN分析表明，多西他赛的清除量与体表面积(BSA，m^2)和血清白蛋白(ALB，g/100ml)呈正相关，与α_1-酸性糖蛋白(AAG，mg/100ml)和年龄呈负相关。谷草转氨酶(GOT)或谷草转氨酶(GPT)升高>60IU/L提示肝功能不全(HEP1=1)的患者，清除能力下降12%。清除量的总体平均值可用方程：CL=BSA(37.0-0.0629AAG-0.192AGE+0.542ALB)(1-0.124HEP1)描述。剩余的个体间变异系数为26%。这些结果与在欧洲和美国人群中获得的结果相当，表明在消除多西他赛方面没有种族差异。药物动力学特征与剂量限制毒性(骨髓抑制)之间的关系符合Sigmoid Emax模型。浓度-时间曲线下面积(AUC)是骨髓抑制严重程度的决定因素。但疗效与AUC值无相关性。本研究结果对优化多西他赛的剂量有一定的参考价值。

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.