The pharmacokinetic modelling of GI198745 (dutasteride), a compound with parallel linear and nonlinear elimination

Aims To characterize the pharmacokinetics of the dual 5 alpha-reductase inh ibitor GI198745 (dutasteride) to allow for more accurate predictions of GI1 98745 concentrations after different dosing schedules. Methods In this randomized, single-blind, parallel group study, 32 healthy male volunteers received single oral doses of GI198745 ranging from 0.01 to 40 mg. Data were analysed by nonlinear mixed effects modelling using NONME M where both linear and nonlinear pharmacokinetic models were examined. Results The time course of GI198745 serum concentrations indicated concentr ation dependent elimination, with the apparent half-life increasing with do se. Data were best described by a two-compartment model with first order ab sorption and parallel linear and nonlinear elimination pathways. Drug absor ption was rapid, and was followed by a short distribution phase. A high vol ume of distribution (511 1) and a low linear clearance (0.58 l h(-1)) combi ned to give a half-life of up to 5 (1-7) weeks at high concentrations. As c oncentrations declined towards K-m (0.96 ng ml(-1)), the proportion elimina ted by the relatively rapid saturable elimination pathway, with a maximum c learance of 6.2 l h(-1), increased and the half-life reduced to about 3 day s. The estimated inter individual variability for the linear clearance was high (CV = 70%). Conclusions GI198745 pharmacokinetics are well described by a pharmacokinet ic model with parallel linear and nonlinear elimination. Simulations using this model show that at daily doses of 0.1 mg the steady state drug concent rations, and the rate at which these are achieved, are mainly influenced by the nonlinear pathway, while at daily doses above 1 mg they are almost ent irely influenced by the linear pathway.