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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.
Publication
Types:
- Clinical
Trial
-
Randomized Controlled Trial
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