Mechanism-based pharmacokinetic model for paclitaxel

Purpose: To create a model based on known mechanisms of paclitaxel distribu tion that could describe the pharmacokinetics (PK) of total and unbound pla sma concentrations, as well as blood concentrations. In addition, to invest igate the relationship between exposure, based on unbound and total concent rations, and neutropenia. Patients and Methods: Paclitaxel and Cremophor EL (CrEL) concentrations wer e obtained from 23 female and three male patients (50 courses in total) wit h different cancer types that received paclitaxel (Taxol; Bristol-Myers Squ ibb Co, Princeton, NJ) (135 to 225 mg/m(2)) as 3- or 24-hour intravenous in fusions. Seven of the patients received combination therapy with doxorubici n or cisplatin. The population PK model was built to fit three types of dat a simultaneously: unbound, total plasma, and blood concentrations. The area under the curve, threshold, and general models were used to relate neutrop hil survival fraction from 19 patients (29 courses in total) to exposure ba sed on unbound and total plasma concentration, respectively. Results: 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 cell s. The threshold model best described the PK/pharmacodynamic (PD) relations hip for total concentration. No distinction could be made between the model s for unbound drug. Conclusion: Earlier PK models for paclitaxel have been empirical. This stud y shows that a mechanistic model can be used to describe the nonlinear PK o f paclitaxel. There is an indication that the PK/PD relationship is not the some for unbound and total plasma concentrations.