Po. Gisleskog et al., The pharmacokinetic modelling of GI198745 (dutasteride), a compound with parallel linear and nonlinear elimination, BR J CL PH, 47(1), 1999, pp. 53-58
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.