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

Abstract

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 1 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 l, 143 l/h and 3150 l, respectively, in the absence or presence of low doses of zosuquidar.3HCl (<500 mg). In the presence of high doses of zosuquidar.3HCl (≥500 mg), these values decreased by 25%, 26%, 48% and 73%, respectively, and doxorubicinol pharmacokinetics were characterized by a delayed t_max (24 h 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 (≥500 mg) and provided insights into the pharmacokinetic interaction, which may be useful in designing future clinical trials.