A model for the turnover of dihydrotestosterone in the presence of the irreversible 5 alpha-reductase inhibitors GI198745 and finasteride.
OBJECTIVE
To develop a pharmacokinetic-pharmacodynamic model that characterizes the conversion of testosterone to dihydrotestosterone (DHT) by 5 alpha-reductase types 1 and 2 and the irreversible inhibition of 5 alpha-reductase by finasteride, a 5 alpha-reductase type 2 inhibitor and by GI198745 (dutasteride), a potent and specific dual 5 alpha-reductase inhibitor.


METHODS
Healthy men (n = 48) received doses of 0.1 to 40 mg GI198745 (n = 4 subjects per dose), 5 mg finasteride (n = 8), or placebo (n = 8) in a parallel-group study. Plasma concentrations of GI198745, finasteride, and DHT were measured frequently up to 8 weeks after dosing. Models were fitted with mixed-effects modeling with the NONMEM program.


RESULTS
The pharmacodynamics were well described with a model that accounted for the rates of DHT formation and elimination, 5 alpha-reductase turnover, relative capacity of the 2 5 alpha-reductase isozymes, and the rates of irreversible inhibition of one (finasteride) or both (GI198745) types of 5 alpha-reductase. The model indicated that type 2 5 alpha-reductase contributed approximately 80% of plasma DHT. GI198745 was about 3-fold more potent than finasteride on 5 alpha-reductase type 2. Nearly full blockade of both isozymes was achieved at doses of 10 mg or more GI198745, although the potency of this agent on 5 alpha-reductase type 1 was less than on type 2.


CONCLUSIONS
A physiologically based model for the turnover and irreversible inhibition of 5 alpha-reductase and for formation and elimination of DHT described the data well. This model helps explain differences in the rates of onset and offset of effect and offers a way to determine the relative potency of the irreversible 5 alpha-reductase inhibitors.
Gisleskog
P O
PO
Division of Clinical Pharmacology, GlaxoWellcome Research and Development, Middlesex, England. po7205@GlaxoWellcome.co.uk
Hermann
D
D
Hammarlund-Udenaes
M
M
Karlsson
M O
MO
D058891:5-alpha Reductase Inhibitors; D000328:Adult; D001378:Azasteroids / Q000494:pharmacology*; D013196:Dihydrotestosterone / Q000378:metabolism*; D000068538:Dutasteride; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018120:Finasteride / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012016:Reference Values; D016037:Single-Blind Method; D013739:Testosterone / Q000378:metabolism
D058891:5-alpha Reductase Inhibitors; D001378:Azasteroids; D004791:Enzyme Inhibitors; D013196:Dihydrotestosterone; D013739:Testosterone; D018120:Finasteride; D000068538:Dutasteride