A population pharmacokinetic model for doxorubicin and doxorubicinol in the presence of a novel MDR modulator, zosuquidar trihydrochloride (LY335979)

Purpose: To develop a population pharmacokinetic model for doxorubicin and doxorubicinol in the presence of zosuquidar.3HCl, a potent P-glycoprotein inhibitor. Methods: The population. approach was used (implemented with NONMEM) to analyse doxorubicin-doxorubicinol pharmacokinetic data from 40 patients who had received zosuquidar.3HCl and doxorubicin intravenously (separately in cycle I and concomitantly in cycle 2 over 48 h and 0.5 h, respectively). Results: A five-compartment pharmacokinetic model (including three compartments for doxorubicin pharmacokinetics with two pathways for doxorubicinol formation) best described the doxorubicin-doxorubicinol pharmacokinetics in the presence of zosuquidar.3HCl. Doxorubicin clearance (CL), peripheral volume of distribution (V2) and doxorubicinol apparent clearance (CLm/fm) and apparent volume of distribution (Vm/fm) were 62.3 l/h, 2360 1, 143 l/h and 3150 1, respectively, in the absence or presence of low doses of zosuquidar.3HCl (<500 mg). In the presence of high doses of zosuquidar.3HCl ( greater than or equal to500 mg), these values decreased by 25%, 26%, 48% and 73%, respectively, and doxorubicinol pharmacokinetics were characterized by a delayed t(max) (24 It versus 4 h), which led to the inclusion of the parallel pathways. A decrease in the objective function (P < 0.005) was observed when the impact of zosuquidar.3HCl was accounted for. Conclusions: This integrated parent-metabolite population pharmacokinetic model. accurately characterized the increase in doxorubicin and doxorubicinol exposure (1.33- and 2-fold, respectively) in the presence of zosuquidar.3HCl (greater than or equal to500 mg) and provided insights into the pharmacokinetic interaction, which may be useful in designing future clinical trials.