H. Neal Bramson, David Hermann, Kenneth W. Batchelor, Frank W. Lee, Michael K. James and Stephen V. Frye.
Department of Clinical Pharmacology (D.H.), Divisions of Biochemistry (H.N.B.) and Metabolic Diseases Research (K.W.B.), Bioanalysis and Drug Metabolism (F.W.L.), and Chemistry (S.V.F.), Glaxo Wellcome Research Institute, Research Triangle Park, North Carolina, and Inspire Pharmaceuticals Inc., Durham, North Carolina (M.K.J.)
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Unique Preclinical Characteristics of GG745, A Potent Dual Inhibitor of 5AR
Selective inhibition of type 2 5-reductase has been shown to be efficacious in the treatment of benign prostatic hyperplasia. Pharmacokinetic and pharmacodynamic results are reported of treatment with a potent inhibitor of both 5-reductase isozymes, GG745, in rats, dogs and men. In the rat, GG745 has a similar effect on DHT-driven prostatic growth as finasteride, another dual 5-reductase inhibitor in this species. However, GG745 appears to be more potent in the rat, a result that likely reflects the greater inherent potency and terminal half-life of GG745 (14 hr) compared with that of finasteride (1 hr). These pharmacokinetic differences are also maintained in the dog (65 and 4 hr for GG745 and finasteride, respectively). From these results, the literature, and in vitro studies, we estimated doses of GG745 likely to prove efficacious in reducing DHT levels in man. These estimated values were predictive of single-dose effects of GG745 in man.
Results from single-dose evaluations in man indicate that GG745 has a terminal half-life of ~240 hr, and single doses of >10 mg decreased DHT levels significantly more than did single 5-mg doses of finasteride. These data support the hypothesis that a molecule (GG745) that effectively inhibits both 5-reductases will lower serum DHT levels significantly more than a molecule that inhibits only a single 5-reductase isozyme (e.g., finasteride, a selective inhibitor of the type 2 enzyme in man).