A model for the turnover of dihydrotestosterone in the presence of the irreversible 5α-reductase inhibitors GI198745 and finasteride

• Published in: Clinical pharmacology and therapeutics 1998-12, Vol.64 (6), p.636-647
• Main Authors: Gisleskog, Per Olsson, Hermann, David, Hammarlund‐Udenaes, Margareta, Karlsson, Mats O.
• Format: Article
• Language: English
• Subjects: 5-alpha Reductase Inhibitors; Adult; Azasteroids - pharmacology; Biological and medical sciences; Dihydrotestosterone - metabolism; Dutasteride; Enzyme Inhibitors - pharmacology; Finasteride - pharmacology; Genital system. Reproduction; Humans; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Reference Values; Single-Blind Method; Testosterone - metabolism
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1016/S0009-9236(98)90054-6

Objective To develop a pharmacokinetic‐pharmacodynamic model that characterizes the conversion of testosterone to dihydrotestosterone (DHT) by 5α‐reductase types 1 and 2 and the irreversible inhibition of 5α‐reductase by finasteride, a 5α‐reductase type 2 inhibitor and by GI198745 (dutasteride), a potent and specific dual 5α‐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, 5α‐reductase turnover, relative capacity of the 2 5α‐reductase isozymes, and the rates of irreversible inhibition of one (finasteride) or both (GI198745) types of 5α‐reductase. The model indicated that type 2 5α‐reductase contributed approximately 80% of plasma DHT. GI198745 was about 3‐fold more potent than finasteride on 5α‐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 5α‐reductase type 1 was less than on type 2. Conclusions A physiologically based model for the turnover and irreversible inhibition of 5α‐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 5α‐reductase inhibitors. Clinical Pharmacology & Therapeutics (1998) 64, 636–647; doi: