A physiologically based pharmacokinetic model of docetaxel disposition: from mouse to man

Purpose: Docetaxel (Taxotere), an important chemotherapeutic agent with shown activity in a broad range of cancers, is being investigated for use in combination therapies and as an antiangiogenic agent. Docetaxel exhibits a complex pharmacologic profile with high interpatient variability. Pharmacokinetic models capable of predicting exposure under various dosing regimens would aid the rational development of clinical protocols. Experimental Design: A pharmacokinetic study of docetaxel at 5 and 20 mg/kg was carried out in female BALB/c mice. Tissues were collected at various time points and analyzed by liquid chromatography-tandem mass spectrometry. Time course tissue distribution and pharmacokinetic data were used to build and validate a physiologically based pharmacokinetic (PBPK) model in mice. Specific and nonspecific tissue partitioning, metabolism, and elimination data were coupled with mouse physiologic variables to develop a PBPK model that describes docetaxel plasma and tissue pharmacokinetic. The PBPK model was then modified with human model variables to predict the plasma distribution of docetaxel. Results: Resulting simulation data were compared with actual measured data obtained from our pharmacokinetic study (mouse), or from published data (human), using pharmacokinetic variables calculated using compartmental or noncompartmental analysis to assess model predictability. Conclusions: The murine PBPK model developed can accurately predict plasma and tissue levels at the 5 and 20 mg/kg doses. The human PBPK model is capable of estimating plasma levels at 30, 36, and 100 mg/m(2). This will enable us to develop and test various dosing regimens (e.g., metronomic schedules and combination therapies) to achieve specific tissue and plasma concentrations to maximize therapeutic benefit while minimizing toxicity.