Molecule of the Month

Dutasteride

In spite of the promise of 5alpha-reductase inhibitors for benign prostatic hyperplasia (BPH), only one compound to date has reached the market: Merck & Co.'s finasteride (Proscar). However, as a selective type 1 isozyme inhibitor, finasteride has proved only moderately effective in treating BPH and more potent compounds are clearly needed. Dutasteride (GI-198745) is a dual inhibitor of 5alpha-reductase type 1 and 2 isozymes which appears to be suitable for use alone or in combination with alpha1-adrenoceptor antagonists for the treatment of BPH and associated symptoms. Glaxo Wellcome is conducting phase III trials of the compound, with plans to file for regulatory approval in the U.S. and Europe this year.

In a randomized, double-blind, parallel group 4-week study, dutasteride (40 mg loading dose then 0.1, 0.5, 2.5 and 2.5 mg/day) was shown to more potently suppress dihydrotestosterone (DHT) as compared to finasteride (5 mg/d) in 53 subjects with benign prostatic hyperplasia. DHT was dose-dependently suppressed in dutasteride-treated subjects with a maximum suppression of 95% occurring with the 5 mg dose; 0.5 mg, the lowest maximally effective dose, decreased DHT levels by 90% at 4 weeks and by 94% at 24 weeks, while finasteride only suppressed levels by 67 and 76%, respectively. Although testosterone levels increased (9-27%) with DHT suppression with both agents, levels were considered normal. Similar incidence of adverse effects was observed for placebo and both treatment groups although decreased libido was observed in subjects given 5 mg finasteride or dutasteride.

In an open-label, crossover study presented this summer to the American Urology Association, 38 healthy male subjects were given the alpha-blocker tamsulosin (0.4 mg/day) or terazosin (titrated up to 10 mg/day) for 14 days, followed by 7-day washout and subsequent treatment with dutasteride (0.5 mg/day following a 40-mg loading dose) for 21 days, followed finally by a 14-day treatment with the combination of dutasteride plus tamoxifen or terazosin. The results showed no significant drug interactions as regards pharmacokinetics. In addition, the incidence of adverse events of headache, dizziness, musculoskeletal pain, orthostasis, nausea and emesis was lower when dutasteride was coadministered with tamoxifen (18% vs. 29%) or terazosin (35% vs. 67%) compared to either drug alone.