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.

A phase II multi-center, double blind, placebo-controlled study was conducted on 416 males with AGA , ages 21 to 45 years, to evaluate the dose response relationship of Avodart (marchio registrato) on hair growth.

Repeated doses of Avodart (marchio registrato) (0.05 mg, 0.1mg, 0.5mg, and 2.5 mg daily) were compared to placebo for 6 months. Safety and tolerability of the varying dose of Avodart (marchio registrato) and finasteride 5 mg daily compared with placebo were also investigated.

The most common drug-related adverse events were decreased libido experienced by 13% of subjects receiving Avodart (marchio registrato) 2.5 mg/day, followed by howdahes experienced by 8% of the Avodart (marchio registrato) 0.1 mg/day group and 6% of the Avodart (marchio registrato) 0.5 mg/day and 2.5 mg/day group.

In studying a 0.79 square inch target mean hair counts decreased for placebo treated patients.

At 24 weeks hair counts were:

62 for Avodart (marchio registrato) 0.05 mg/day,

66 for Avodart (marchio registrato) 0,1 mg/day,

95.5 for Avodart (marchio registrato) 0.5 mg/day,

109.8 for Avodart (marchio registrato) 2.5 mg/day,

73.2 for finasteride 5 mg/day,

-29.6 for placebo.


Avodart (marchio registrato) was discontinued at the 24 week mark. Hair counts were then reassessed at the 36 week mark (12 weeks after stopping Avodart (marchio registrato) and Finasteride). Mean hair counts decreased for Avodart (marchio registrato) 0.05 mg/day, Avodart (marchio registrato) 0.1 mg/day, Finasteride 5 mg/day and placebo during the drug free time. Improvement in hair counts was maintained for Avodart (marchio registrato) 0.5 mg/day and Avodart (marchio registrato) 2.5 mg/day 12 weeks after discontinuing the medication.

In studying a 0.79 square inch target mean hair counts decreased for placebo treated patients progressively.

At 36 weeks (12 weeks after stopping Avodart (marchio registrato) and Finasteride) hair counts were:

-17.1 for Avodart (marchio registrato) 0.05 mg/day,

16.8 for Avodart (marchio registrato) 0,1 mg/day,

84.3 for Avodart (marchio registrato) 0.5 mg/day,

119.8 for Avodart (marchio registrato) 2.5 mg/day,

13.2 for finasteride 5 mg/day,

-37.3 for placebo.

SOURCE OF FUNDING

GlaxoWellcome Research and Development.

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