EFFECTIVE SUPPRESSION OF
DIHYDROTESTOSTERONE (DHT) BY DUTASTERIDE, A NOVEL, DUAL 5
ALPHA REDUCTASE INHIBITOR.
Richard V Clark, David J Hermann, Hoda Gabriel, Timothy H
Wilson, Betsy B Morrill, and Stuart Hobbs.
Research Triangle Park, NC (presented by Dr. Clark)
INTRODUCTION AND OBJECTIVES
DHT is formed from testosterone (T) by Type 1 and Type 2 5 a
reductase enzyme (5AR). DHT plays a key role
in the development and progression of benign prostatic
hyperplasia (BPH). Dutasteride is the first dual inhibitor of
both 5AR isozymes. We compared hormonal effects of dutasteride
with placebo and finasteride, a Type 2 5AR inhibitor.
METHODS
One group of 53 subjects was studied for 4 weeks and received
dutasteride at 0.1, 0.5, 2.5, 5.0mg and 2.5mg
with a 40mg loading dose, placebo, or 5mg finasteride daily. A
second group of 313 subjects was studied for 24 weeks and
received dutasteride at 0.01, 0.05, 0.5, 2.5, or 5.0mg,
placebo, or 5mg finasteride daily. Studies
were randomized, double blinded, with a parallel group design.
All subjects had BPH, prostate volume >= 30ml
or IPSS >= 8. Dutasteride groups were compared to placebo
and finasteride by a general linear model with
pairwise comparisons, and a sigmoid Emax model for DHT dose
response.
RESULTS
Dutasteride suppressed DHT in dose related fashion with
maximal suppression >= 95% at the 5.0mg dose. The lowest
maximally effective dose was 0.5mg, with 90% DHT suppression
at 4 wks, increasing to 94% at 24 wks, while finasteride
suppressed DHT by 67% and 76% respectively. T rose in
conjunction with DHT suppression, ranging from 9 to 27%, but
mean T levels with both dutasteride and finasteride remained
within the normal range.
Laboratory studies and ECG's remained normal during the
studies. Adverse events were typical, non-specific
events and were reported at comparable rates to placebo for
both compounds, except for decreased libido with 5.0mg
dutasteride and finasteride.
CONCLUSIONS
Dutasteride, a dual inhibitor of 5AR, achieved significantly
greater suppression of DHT with less subject
variability compared to finasteride. The increase in T at
maximally effective doses of dutasteride was not
considered clinically significant as mean T levels remained in
the normal range. Dutasteride was well tolerated at all dose
levels studied with a safety profile comparable to placebo
except for a mild decrease in libido also noted with
finasteride. The consistent and increased suppression of DHT
by dutasteride may show greater clinical benefit in the
treatment of BPH. This is currently being investigated with
the 0.5mg dose in large-scale phase III clinical trials.
SOURCE OF FUNDING
GlaxoWellcome Research and Development. |
