1Per Olsson, 1David Hermann, 2Margareta Hammarlund-Udenaes, 2Mats O Karlsson
Pharmacokinetics and Dynamics, GlaxoWellcome Research and Development, Middlesex, UK 2Division of Biopharmaceutics and Pharmacokinetics, Department of Pharmacy, Uppsala University, Uppsala, Sweden
Dihydrotestosterone (DHT) is thought to be the androgen primarily responsible for the development of benign prostatic hyperplasia. Testosterone is converted to DHT by 5alpha-reductase (5AR) types 1 and 2. Treatment of patients with finasteride, a selective type 2 5AR inhibitor, reduces circulating DHT concentrations by 60-80%. A potent and specific dual 5AR inhibitor, GI198745 (17beta-N-(2,5 bis(trifluormethyl) phenylcarbamoyl)-4-aza-5alpha-androst-1-en-3-one) has been developed. To aid optimisation of therapy, we have developed a mechanistic model for the irreversible inhibition of 5AR and the subsequent effect on DHT levels.
The model was based on data from 36 healthy males participating in a parallel group study with doses of 0.1 to 40 mg GI198745 (n=4 per dose) or 5 mg finasteride (n=8). Plasma concentrations of GI198745, finasteride and DHT were measured frequently at up to 8 weeks after dosing.
The PK and PK/PD analyses were performed sequentially. The pharmacokinetics were analysed using a linear two compartment, first order absorption model for finasteride and a two compartment, first order absorption model with parallel linear and saturable elimination for GI198745. The pharmacodynamic model accounted for the rates of DHT formation and elimination, 5AR turnover, the relative capacity of the two 5AR isozymes and the rates of irreversible inhibition of one (finasteride) or both (GI198745) types of 5AR.
The model indicated that type 2 5AR contributed to ca 80% of plasma DHT. GI198745 was about 3-fold more potent on 5AR type 2 than was finasteride. The potency of GI198745 on 5AR type 1 was less, but near full blockade of both isozymes was achieved by GI198745 at the higher doses. For finasteride the rate of return to baseline DHT levels was mainly determined by the rate of 5AR turnover but for the higher doses of GI198745 it was determined by the rate of drug elimination. Using the developed model, different dosing schedules for GI198745 were investigated.
Reference: PAGE 6 (1997) Abstr 584 [www.page-meeting.org/?abstract=584]
Poster: oral presentation