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.
