Henningsson A, Karlsson M O, Viganò L, Gianni L, Verweij J, Sparreboom A
Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Faculty of Pharmacy, Uppsala University, Sweden.
J Clin Oncol. 2001 Oct 15;19(20):4065-73. doi: 10.1200/JCO.2001.19.20.4065.
To create a model based on known mechanisms of paclitaxel distribution that could describe the pharmacokinetics (PK) of total and unbound plasma concentrations, as well as blood concentrations. In addition, to investigate the relationship between exposure, based on unbound and total concentrations, and neutropenia.
Paclitaxel and Cremophor EL (CrEL) concentrations were obtained from 23 female and three male patients (50 courses in total) with different cancer types that received paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ) (135 to 225 mg/m(2)) as 3- or 24-hour intravenous infusions. Seven of the patients received combination therapy with doxorubicin or cisplatin. The population PK model was built to fit three types of data simultaneously: unbound, total plasma, and blood concentrations. The area under the curve, threshold, and general models were used to relate neutrophil survival fraction from 19 patients (29 courses in total) to exposure based on unbound and total plasma concentration, respectively.
The PK model included a linear three-compartment model for unbound concentration, binding directly proportional to CrEL, linear and nonlinear binding to plasma proteins, and linear and nonlinear binding to blood cells. The threshold model best described the PK/pharmacodynamic (PD) relationship for total concentration. No distinction could be made between the models for unbound drug.
Earlier PK models for paclitaxel have been empirical. This study shows that a mechanistic model can be used to describe the nonlinear PK of paclitaxel. There is an indication that the PK/PD relationship is not the same for unbound and total plasma concentrations.
基于已知的紫杉醇分布机制创建一个模型，该模型能够描述总血浆浓度、游离血浆浓度以及血药浓度的药代动力学（PK）。此外，研究基于游离浓度和总浓度的暴露与中性粒细胞减少之间的关系。
从23名女性和3名男性患者（共50个疗程）中获取紫杉醇和聚氧乙烯蓖麻油（CrEL）浓度，这些患者患有不同类型的癌症，接受紫杉醇（泰素；百时美施贵宝公司，新泽西州普林斯顿）（135至225mg/m²），静脉输注3小时或24小时。其中7名患者接受了阿霉素或顺铂联合治疗。构建群体PK模型以同时拟合三种类型的数据：游离、总血浆和血药浓度。分别使用曲线下面积、阈值和通用模型，将19名患者（共29个疗程）的中性粒细胞存活分数与基于游离和总血浆浓度的暴露相关联。
PK模型包括一个用于游离浓度的线性三室模型，与CrEL直接成比例结合，与血浆蛋白的线性和非线性结合，以及与血细胞的线性和非线性结合。阈值模型最能描述总浓度的PK/药效学（PD）关系。对于游离药物的模型之间无法区分。
早期的紫杉醇PK模型是经验性的。本研究表明，一个机制模型可用于描述紫杉醇的非线性PK。有迹象表明，游离血浆浓度和总血浆浓度的PK/PD关系不同。
