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The pharmacokinetic modelling of GI198745 (dutasteride), a compound with parallel linear and nonlinear elimination
Author(s) -
Gisleskog Per Olsson,
Hermann David,
HammarlundUdenaes Margareta,
Karlsson Mats O.
Publication year - 1999
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.1999.00843.x
Subject(s) - pharmacokinetics , nonmem , elimination rate constant , volume of distribution , chemistry , pharmacology , dutasteride , half life , distribution (mathematics) , absorption (acoustics) , mathematics , medicine , materials science , prostate , mathematical analysis , composite material , cancer
Aims To characterize the pharmacokinetics of the dual 5α‐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 K m (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=70%).Conclusions GI198745 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.