To characterize the pharmacokinetics of the dual
5alpha-reductase inhibitor GI198745 (dutasteride)
to allow for more accurate predictions of GI198745
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 NONMEM where both linear
and nonlinear pharmacokinetic models were examined.
RESULTS: The time course of GI198745 serum concentrations
indicated concentration dependent elimination, with
the apparent half-life increasing with dose. Data
were best described by a two-compartment model with
first order absorption and parallel linear and nonlinear
elimination pathways. Drug absorption was rapid,
and was followed by a short distribution phase.
A high volume of distribution (511 l) and a low
linear clearance (0.58 l h(-1)) combined to give
a half-life of up to 5 (1-7) weeks at high concentrations.
As concentrations declined towards Km (0.96 ng ml(-1)),
the proportion eliminated by the relatively rapid
saturable elimination pathway, with a maximum clearance
of 6.2 l h(-1), increased and the half-life reduced
to about 3 days. The estimated inter individual
variability for the linear clearance was high (CV
G1198745 pharmacokinetics are well described by
a pharmacokinetic model with parallel linear and
nonlinear elimination. Simulations using this model
show that at daily doses of 0.1 mg the steady state
drug concentrations, 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 entirely influenced by the linear pathway.