Preliminary studies with MK386 a type 1 5areductase inhibitor

Separate studies were conducted with a type 1-selective 5aR inhibitor to determine utility of this mechanism of action, which differs from that of finasteride in inhibiting the alternate isoenzyme of 5aR, in the treatment of clinical disorders. Based on the known stimulation of acne by androgens (Hamilton 1941) and tissue localization of the type 1 isoenzyme (Harris et al. 1992; Thiboutot et al. 1995), which is prominent in sebaceous glands of the skin, a potential target for intervention was in the treatment of patients with acne vulgaris.

18.8.1 Effects on serum and sebum DHT

Studies conducted in normal volunteers confirmed that the type 1-selective 5aR inhibitor, MK-386 (Merck & Co., Inc.) (Fig. 18.6), reduced serum DHT concentrations by approximately 30% when administered once daily orally (Ellsworth etal. 1996; Schwartz etal. 1996). Oral administration ofMK-386 also reduced sebum

Type 2-selective 5aR inhibitor (finasteride)

Type 1-selective 5aR inhibitor (MK-386)

Non-selective 5aR inhibitor (dutasteride)

Type 2-selective 5aR inhibitor (finasteride)

Type 1-selective 5aR inhibitor (MK-386)

Non-selective 5aR inhibitor (dutasteride)

Fig. 18.6 Structures of type 2-selective, type 1-selective and non-selective 5a-reductase inhibitors (Harris and Kozarich 1997).

DHT concentrations by approximately 50%, based on a standardized, validated method for measuring sebum output (Schwartz et al. 1997). In a separate study, Imperato-McGinley and co-workers demonstrated no difference in sebum output between subjects with type 2 5aR deficiency and normals, and included subjects with androgen insensitivity as a 'positive control', who, as expected, demonstrated no measurable sebum output over the measurement period (Imperato-McGinley et al. 1993). These findings led to the hypothesis that treatment with a type 1-selective 5aR inhibitor could have utility in the treatment of patients with acne. However, a placebo- and active-controlled clinical proof of concept study with MK-0219 (Merck & Co, Inc.), another type 1-selective 5aR inhibitor, in patients with acne vulgaris failed to demonstrate utility in this disorder (Leyden etal. 2004). To date, no type 1-selective 5aR inhibitors have been brought through clinical development to marketing approval. Effects in combination with finasteride

Studies conducted in normal volunteers evaluated the effects of concomitant administration of finasteride (a type 2-selective 5aR inhibitor) and the type 1-selective 5aR inhibitor, MK-386. Administration of finasteride for seven days produced ~65% reduction in circulating DHT, as expected. Subsequent dosing of MK-386 co-administered with finasteride demonstrated additivity of DHT reduction, producing near complete suppression (~95%) of circulating DHT (Schwartz et al. 1996). These data were consistent with the prior observation, obtained from patients with type 2 5aR deficiency, that there are two separate 5aR enzymes contributing to circulating DHT, with the type 2 5aR isoenzyme contributing ~2/3 of circulating DHT while the type 1 isoenzyme contributed ~1/3. Further, the results of this study confirmed that isoenzyme-specific 5aR inhibitors can be used selectively or in combination in vivo. The near-complete suppression of circulating DHT observed with co-administration of type 1- and type 2-selective 5aR inhibitors argues against the likelihood of a third, as yet undiscovered, 5aR isoenzyme in man.

18.9 Future research

18.9.1 Long-term study of finasteride in chemoprevention of prostate cancer

Preclinical studies in animals and in cell lines in vitro support the concept that DHT is an important promoter of prostatic growth and, potentially, of prostate cancer (Gormley 1991; Gormley etal. 1995). At present, no 5aR inhibitor is indicated for use in the prevention or treatment of prostate cancer. Recently, the results of the Prostate Cancer Prevention Trial (PCPT), sponsored by the U.S. National Cancer Institute (NCI) and coordinated by the Southwest Oncology Group (SWOG), were released (Feigl etal. 1995; Gormley etal. 1995; Thompson etal. 1997; 2003). This landmark study randomized (1:1) 18,882 men >55 years of age with no evidence of prostate cancer (normal prostate exam; serum prostate-specific antigen (PSA) level <3.0 ng/mL) to treatment with finasteride 5 mg per day or matching placebo. All men were to be evaluated for the presence of prostate cancer by needle biopsy of the prostate, either based on signs or symptoms suggestive of prostate cancer during the study or at the end of the study. The trial was stopped early due to premature attainment of the primary endpoint: a 25% reduction in the period prevalence of prostate cancer was observed in the group treatedwith finasteride5 mg compared to the group treated with placebo (prostate cancer diagnosed in 18.4% of finasteride-treated subjects compared to 24.4% of placebo). However, a slightly higher percentage of subjects with Gleason grade 7-10 prostate cancer was reported in the finasteride group compared to the placebo group (6.4% vs. 5.1%). While the trial confirmed its primary hypothesis that chronic suppression of intraprostatic DHT reduces the incidence of prostate cancer, the implications of the secondary finding are less well defined. For example, it is not known whether the increase in the percent of patients with Gleason grade 7-10 prostate cancer represents tumors that are clinically more aggressive. Hypotheses to explain the secondary finding include: (1) selection for development of high-grade tumors due to the effects of finasteride; (2) detection bias, favoring diagnosis of higher grade tumors in the finasteride group (i.e., finasteride treatment suppresses low-grade tumors without suppressing high-grade tumors, combined with enhancement of prostate cancer detection by needle biopsy due to finasteride-induced prostate gland shrinkage); and (3) altered histologic appearance, towards appearance of less differentiation of prostate cancer tissue obtained by needle biopsy due to treatment with finasteride. The latter hypothesis is supported by reports of prostatic tissue atrophy and cell apoptosis associated with finasteride treatment (Rittmaster et al. 1996), and is a well-documented phenomenon associated with antiandrogen therapy in patients with prostate cancer. Further analyses of data from the PCPT may clarify which of these hypotheses, if any, clarify this secondary finding.

18.9.2 Development of other 5a-reductase inhibitors

Since the development of finasteride, only one other 5aR inhibitor has been marketed for clinical use. Dutasteride ((5a,17^)-N-{2,5 bis(trifluoromethyl) phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide), a non-selective 5aR inhibitor from GlaxoSmithKline with affinity for both the type 1 and type 2 5aR isoenzymes in man (Bramsen et al. 1997) (Fig. 18.6), was approved for marketing in 2001 at a 0.5 mg daily dose (Avodart™) as a treatment for men with benign pro-static hyperplasia. While studies with dutasteride have also been conducted in men with AGA, definitive studies in this population have not been completed and the drug has not been approved for the treatment of men with this disorder. In clinical studies in men with BPH, dutasteride demonstrates an efficacy and safety profile that appears to be generally similar to that of finasteride 5 mg (U.S. Product Circular for AvodartR, 2002). However, long-term studies covering more than two years have not been published, and there is no genetic model of dual (or of type 1) 5aR inhibition from which to obtain information regarding the implications of chronic inhibition of both 5aR isoenzymes in man. Other 5aR inhibitors have been synthesized and subsequently tested in clinical trials (Bakshi etal. 1995; Hirsch etal. 1993; Jones etal. 1993; Kojo etal. 1995; Levy etal. 1994; Nakayama etal. 1997; Ohtawa et al. 1991; Van Hecken et al. 1994), but to date none has reached marketing approval.

18.10 Key messages

• The development of 5aR inhibitors which followed the identification of a putative role for DHT, a key metabolite of testosterone, in the pathogenesis of androgen-dependent disorders of adult men has significantly expanded our understanding of androgen biology and contributed to novel treatments for patients.

• Finasteride, the first marketed 5aR inhibitor, is selective for the type 2 isoenzyme in man and is marketed for the treatment of men with BPH at a 5 mg daily dose and for the treatment of men with AGA at a 1 mg daily dose.

• Recently, dutasteride, a non-selective 5aR inhibitor, was approved for marketing for the treatment of men with BPH.

• No type 1-selective 5aR inhibitors have been brought through clinical development to marketing approval.

• Currently, there are no approved uses for 5aR inhibitors in women.

• Future developments, such as detailed understanding of the molecular mechanisms underlying the discrete actions of specific androgens, such as testosterone and DHT, offer the promise of greater insight into the pathogenesis of androgen-mediated disorders in affected patients.


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