| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
-Reductase Inhibitor
Clinical Pharmacology (R.V.C., D.J.H.) and Clinical Development (T.H.W., B.B.M., S.H.), GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709; and Department of Medicine and Endocrinology (G.R.C.), Baylor College of Medicine, Houston, Texas 77030
Address all correspondence and requests for reprints to: Richard V. Clark, M.D., Ph.D., Clinical Pharmacology–Metabolic Discovery Medicine, 17.1356H, GlaxoSmithKline Research and Development, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709. E-mail: richard.v.clark{at}gsk.com.
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
-reductase, which exists in two isoenzyme forms (types 1 and 2). DHT is associated with development of benign prostatic hyperplasia (BPH), and reduction in its level with 5-reductase inhibitors improves the symptoms associated with BPH and reduces the risk of acute urinary retention and prostate surgery. A selective inhibitor of the type 2 isoenzyme (finasteride) has been shown to decrease serum DHT by about 70%. We hypothesized that inhibition of both isoenzymes with the dual inhibitor dutasteride would more effectively suppress serum DHT levels than selective inhibition of only the type 2 isoenzyme. A total of 399 patients with BPH were randomized to receive once-daily dosing for 24 wk of dutasteride (0.01, 0.05, 0.5, 2.5, or 5.0 mg), 5 mg finasteride, or placebo. The mean percent decrease in DHT was 98.4 ± 1.2% with 5.0 mg dutasteride and 94.7 ± 3.3% with 0.5 mg dutasteride, significantly lower (P < 0.001) and with less variability than the 70.8 ± 18.3% suppression observed with 5 mg finasteride. Mean testosterone levels increased but remained in the normal range for all treatment groups. Dutasteride appeared to be well tolerated with an adverse event profile similar to placebo.
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
-reductase is the primary active metabolite of testosterone (1). In male fetal development and puberty, it is essential for normal masculinization of the external genitalia and normal development of the prostate gland. In later life, DHT is associated with the development of benign prostatic hyperplasia (BPH) and androgenetic alopecia.
The enzyme 5-reductase is present throughout the body in two forms, type 1 and type 2 (2). Type 1 has been reported to be located predominantly in the skin, both in hair follicles and sebaceous glands, as well as in the liver, prostate, and kidney (3, 4, 5). Type 2 is found in the male genitalia and the prostate (6, 7, 8); recent research has also identified type 1 mRNA and enzyme activity in the prostate (9, 10, 11).
The role of DHT in male fetal development was recognized when a deficiency of the type 2 5-reductase isoenzyme was described in association with a clinical syndrome characterized by male pseudohermaphroditism (12, 13). These individuals are born with impaired masculinization of the external genitalia and a rudimentary prostate. In later life, they do not develop BPH or prostate cancer (14, 15). This lack of development of BPH led to the development of an inhibitor of 5-reductase to treat this common condition (16). The first available 5-reductase inhibitor (finasteride) is selective for the type 2 isoenzyme (17). Its clinical utility in reducing enlarged prostates, relieving symptoms associated with BPH, and reducing the risk of associated complications has been documented in several clinical trials (18, 19). More recently, 5-reductase inhibition has been proven effective in treating androgenetic alopecia (20). Finasteride suppresses serum DHT by about 70% (21).
Dutasteride is a 6-azasteroid, which inhibits both type 1 and type 2 5-reductase isoenzymes. The IC50 for type 1 5-reductase is 0.7 and 81.0 nM for dutasteride and finasteride, respectively, and for type 2 5-reductase, 0.05 and 0.16 nM, respectively (22). Based on animal studies and preliminary studies in man, it was hypothesized that a dual inhibitor of 5-reductase would suppress DHT levels more effectively than a selective type 2 inhibitor. This phase II dose-response study was undertaken to test this hypothesis.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
The study (ARIA2001) was a double-blind, placebo-controlled, parallel group evaluation of five dosing regimens of dutasteride and finasteride. Patients received 24 wk of once-daily treatment with placebo, dutasteride (0.01, 0.05, 0.5, 2.5, or 5.0 mg) or 5.0 mg finasteride (recommended daily dose for BPH), followed by a 16-wk postdosing assessment period. Study end points were: serum DHT, testosterone, and LH levels; dutasteride pharmacokinetics; and safety and tolerability based on standard laboratory studies and adverse event reporting. Patients were assessed at 4-wk intervals during the active- and posttreatment periods. DHT and testosterone were measured in all patients at baseline and after 24 wk of treatment. In addition, a subset of 12 patients per treatment arm had DHT and testosterone assessments at wk 4, 8, 12, 16, and 20 of treatment and wk 4, 8, 12, and 16 post treatment. An additional subset of 20 patients in the placebo, 0.5-mg dutasteride, and finasteride groups had serum LH measured at baseline and wk 24. Investigators were instructed to collect all blood samples in the morning.
Study population
A total of 399 male patients were enrolled at 33 medical centers in the United States and Canada. All centers had approval for this study from their institutional review board or equivalent, and all patients signed informed consents before beginning the study. Patients were 50 yr of age and older with a prior diagnosis of BPH according to medical history and physical examination and a baseline prostate volume of 30 cc and greater.
Statistics
Statistical analyses and summaries were performed with SAS software (version 6, SAS Institute, Cary, NC) for demographics, pharmacodynamic, and safety data. These analyses were performed using two-sided tests of significance with comparisons between placebo and each of the six active treatment groups and between finasteride and the five dutasteride treatment groups. The reported P values for analyses correspond to these pairwise comparisons. Dose response and pharmacokinetic analyses were performed using WinNonlin Pro, version 1.5 (Pharsight Corporation, Mountain View, CA) and SAS software, version 6, to generate a sigmoid Emax model. The primary analysis of DHT focused on percent change from baseline. Treatment groups were compared in terms of percent change from baseline by logarithmically transformed data using a general linear model:
 |
 |
Hormonal and dutasteride assays
Serum DHT levels were measured by a validated gas chromatography/mass spectrometry assay after derivatization (PPD-Pharmaco, Richmond, VA). Intra- and interassay coefficients of variation were 11.6 and 19.2%, respectively. The detection limit of the assay was between 1 and 10 pg/ml, depending on the particular assay run. Calibration curves resulted in correlation coefficients of r 
0.99 over the standard concentration range of 10–1000 pg/ml.
Serum concentrations of testosterone were measured by a central laboratory using a validated, solid-phase RIA method (Diagnostic Products Corp., Los Angeles, CA). Intra- and interassay coefficients of variation were 9.8 and 10.5%, respectively. The detection limit of the assay was 8.0 ng/dl. LH was measured by a central laboratory using a validated immunochemiluminometric assay (Endocrine Sciences, Calabasas Hills, CA). The intra- and interassay coefficients of variation were 4.7 and 10.7%, respectively. The detection limit of the assay was 0.1 mIU/ml.
Serum concentrations of dutasteride were measured by a validated liquid chromatography/atmospheric pressure chemical ionization/mass spectrometry detection assay after protein precipitation (Biomet Division, Glaxo Wellcome R&D, Research Triangle Park, NC) (23). Intraassay precision was 
6.4%, and interassay accuracy expressed as percent nominal concentration was within 95.9–101.1%. Calibration curves resulted in correlation coefficients of r 0.994 over the standard concentration range of 0.5–500 ng/ml.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
A total of 323 patients (81%) completed the 24-wk treatment phase and 305 patients (76%) completed both the treatment and follow-up phases. Across treatment groups, mean age was 62.6–65.5 yr and mean prostate volume was 41.9–47.3 cc (as measured by transrectal ultrasound). The proportion of subjects that discontinued during the treatment phase ranged from 11 to 25% across the treatment groups, and discontinuation in the active treatment groups was not higher than placebo. Of the 76 subjects (19%) who withdrew from the treatment phase, 25 withdrew due to adverse events (nine considered drug related), 10 failed to return to clinic for follow-up visits, five withdrew for lack of improvement in BPH symptoms, and 36 withdrew for other reasons.
DHT serum concentrations
After 24 wk of treatment, suppression of DHT was observed with a clear dose-response curve for percent change from baseline for the dutasteride treatment groups (Fig. 1
). Adjusted mean ± SD decreases in DHT from baseline for the dutasteride treatment groups were as follows: 98.4 ± 1.2% (5.0 mg); 97.7 ± 2.0% (2.5 mg); 94.7 ± 3.3% (0.5 mg); 52.9 ± 22.1% (0.05 mg); and 7.5 ± 26.6% (0.01 mg). Of note is the reduction in variability (SD bars) with increase in dutasteride dose. In comparison, the adjusted mean decrease in DHT with finasteride was 70.8 ± 18.3%. The percent changes in DHT from baseline for dutasteride doses of 0.5, 2.5, and 5.0 mg were significantly greater than placebo (P < 0.001) and finasteride (P < 0.001). These results are summarized in Table 1.
|
|
The time courses of the changes in mean percent DHT levels for the different treatment groups during the study are shown in Fig. 2. Mean percent DHT levels returned to within 20% of baseline with dutasteride at 0.05 mg and finasteride at wk 4 post treatment and for dutasteride at 0.5 mg at wk 16 post treatment. With the highest doses of dutasteride, 2.5 and 5.0 mg, the mean percent DHT levels remained suppressed by 85% or more from baseline at 16 wk post treatment.
|
Testosterone levels increased in conjunction with DHT suppression for all dutasteride groups and the finasteride group. Serum testosterone concentrations did not exceed the upper limits of the normal range except in one individual in each of the placebo, 5-mg dutasteride, and finasteride groups. The increases in adjusted mean serum testosterone ranged between 4 and 21%, with statistically significant differences from placebo seen with 0.5 mg dutasteride (21.2 ± 37.8%) and 2.5 mg dutasteride (19.0 ± 50.3%) (Table 1
).
LH serum concentrations
Baseline LH levels were variable: 6.3 ± 3.5 mIU/ml in the placebo group, 4.5 ± 1.9 mIU/ml in the finasteride group, and 6.9 ± 3.8 mIU/ml in the 0.5-mg dutasteride group. The placebo group showed an adjusted mean decrease from baseline of 0.9 ± 1.4 mIU/ml. Observed were small increases of 0.3 ± 2.7 mIU/ml for dutasteride at 0.5 mg and 0.2 ± 1.4 mIU/ml for finasteride, which were not significantly different from placebo.
Dutasteride serum concentrations
Dutasteride was eliminated in a nonlinear fashion, with a clearance rate of 0.83–1.54 liters/h and a large volume of distribution of 300–500 liters. Mean dutasteride serum concentrations after 24 wk of dosing are presented in Table 1. As dose increased, time to reach steady state increased from 4 to 8 wk in the dutasteride 0.05-mg group to more than 24 wk in the dutasteride 2.5- and 5.0-mg groups. In the 0.5-mg dutasteride group, the majority of patients reached steady state at 24 wk with a serum concentration of 38 ± 13 ng/ml. After discontinuing treatment with dutasteride, the time to reach undetectable dutasteride serum levels in the dutasteride groups receiving 0.01 and 0.05 mg was less than 4 wk, and this increased to more than 16 wk for the dutasteride 2.5- and 5.0-mg groups. After discontinuing 0.5 mg dutasteride, 75% of patients had undetectable levels of dutasteride (quantifiable limit of 0.5 ng/ml) at 16 wk post treatment.
Adverse events
Dutasteride was well tolerated and generally had an adverse event profile similar to placebo. Figure 3 displays the percent of patients in each treatment group that reported any adverse event, had an adverse event considered by the investigator to be drug related, had a serious adverse event, or withdrew from the study due to an adverse event. In these categories, no significant differences from placebo were observed for any of the treatment groups, except for an increased reporting of serious adverse events with 0.01 mg dutasteride (P = 0.032). None of the serious adverse events were considered by the investigators to be drug related.
|
). There were no significant differences in the reporting of the most common adverse events between the active treatment groups and the placebo group apart from the increased reporting of altered libido in the highest-dose dutasteride group (5 mg) and the finasteride group, which both had similar reporting rates.
|
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
-reductase isoenzymes with dutasteride can result in greater and more consistent suppression of serum DHT than that observed with the selective inhibitor of type 2 5-reductase, finasteride. The higher doses of dutasteride (2.5 and 5.0 mg) induced almost complete suppression of DHT at 98.4%, compared with 70.8% with finasteride, consistent with other studies reported in the literature for finasteride (21, 24, 25). The lowest maximally effective dose of dutasteride (0.5 mg) resulted in DHT suppression of 94.7%.
The relative importance of type 1 and type 2 5-reductase in promoting prostate growth has yet to be fully defined. Although both mRNA and enzyme activity consistent with type 1 5-reductase have been found in the prostate, the type 2 isoenzyme predominates in this organ (26). Selective inhibition of type 2 5-reductase by finasteride reduces DHT levels in prostate tissue homogenates by 80% (26). However, the effect of type 1 5-reductase inhibition has not been determined, and local effects on specific cell types and disruption of paracrine signals may be significant.
Studies with 5-reductase have highlighted differences between the two major androgens: testosterone and DHT. Whereas testosterone is largely responsible for muscle development, libido, and potency, DHT is essential for prostate growth and its effects on hair follicles can lead to androgenetic alopecia (27). Whereas DHT can act as a potent androgen, DHT does not appear to be essential in the adult male. Skeletal muscle has little 5-reductase activity, so testosterone is thought to be the major androgen in this tissue, although circulating DHT may contribute a minor effect in normal men. Treatment with finasteride for 4 yr has not shown an adverse effect on bone mineral density associated with decreased DHT levels (28). The short-term safety data in the present study appear to support the tolerability of reduced DHT levels because no unexpected adverse events were reported in conjunction with the almost complete suppression of DHT. Although mean serum testosterone levels rose in association with DHT suppression, testosterone concentrations did not exceed the normal range. This safety profile is further supported by phase III studies with dutasteride (29).
Testosterone, DHT, estradiol, and progesterone all feedback at the hypothalamus and pituitary level to control gonadotropin secretion. Selective inhibition of type 2 5-reductase in man has little effect on serum gonadotropin levels or the LH response to GnRH (30). Although DHT levels in this study were markedly suppressed, and testosterone levels increased within the normal range, LH levels showed little change. These results support the hypothesis that there is minimal change in overall androgenic activity with dual inhibition of type 1 and type 2 5-reductase by dutasteride. The fall in DHT and the rise in testosterone seem to balance with no change in gonadotropin levels, and by inference, no evidence of a change in hypothalamic perception of androgenic feedback, suggesting possible androgen deficiency.
In conclusion, this phase II study has demonstrated that dual inhibition of 5-reductase can result in almost complete suppression of serum DHT levels. Potentially beneficial implications of such marked suppression of DHT are under investigation for overall prostatic health.
|
Footnotes |
|---|
Received February 26, 2003.
Revised December 17, 2003.
Accepted January 23, 2004.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
-reductase: two genes/two enzymes. Annu Rev Biochem 63:25–61[Medline]
-reductase exhibits regional differences in isolated sebaceous glands and whole skin. J Invest Dermatol 105:209–214[CrossRef][Medline]
-reductase type I and II, aromatase, and androgen receptor in hair follicles of women and men with androgenetic alopecia. J Invest Dermatol 109:296–300[CrossRef][Medline]
-reductase. J Clin Invest 89:293–300
-reductase 2 deficiency. J Clin Invest 90:799–809
-reductase isozyme expression. J Clin Invest 92:903–910
-reductase types I and II mRNAs in human hyperplastic prostate and in prostate primary cultures. J Endocrinol 156:509–517[Abstract]
-reductase isozyme gene expression in the human prostate and preputial skin. J Urol 160:577–582[CrossRef][Medline]
-reductase isozyme enzymatic activity in the human prostate. J Urol 161:332–337[CrossRef][Medline]
-reductase deficiency in man: an inherited form of male pseudohermaphroditism. Science 186:1213–1215-reductase deficiency. J Clin Endocrinol Metab 75:1022–1026[Abstract]
-reductase 2 deficiency. Endocr Rev 14:577–593-Reductase inhibitors. J Androl 18:582–587-reductase inhibitor, on circulating androgens in male volunteers. J Clin Endocrinol Metab 70:1136–1141-reductase inhibitor. Steroids 56:469–471[CrossRef][Medline]
-reductase, alone and in combination with finasteride, on serum dihydrotestosterone concentrations in men. J Clin Endocrinol Metab 81:2942–2947-reductase, suppresses prostatic dihydrotestosterone in men with benign prostatic hyperplasia. J Clin Endocrinol Metab 74:505–508[Abstract]
-reductase inhibition with finasteride on bone mineral density in men: results of a 4-year placebo controlled trial. J Urol 167:2105–2108[CrossRef][Medline]
reductase enzyme types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia (BPH). Urology 60:434–441[CrossRef][Medline]
-reductase inhibitor, on serum gonadotropins in normal men. J Clin Endocrinol Metab 75:484–488[Abstract]This article has been cited by other articles:
 |
|
 |
|
  B. S. Kramer, K. L. Hagerty, S. Justman, M. R. Somerfield, P. C. Albertsen, W. J. Blot, H. Ballentine Carter, J. P. Costantino, J. I. Epstein, P. A. Godley, et al. Use of 5-{alpha}-Reductase Inhibitors for Prostate Cancer Chemoprevention: American Society of Clinical Oncology/American Urological Association 2008 Clinical Practice Guideline J. Clin. Oncol., March 20, 2009; 27(9): 1502 - 1516. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. W. Brawley, S. Lucia, and G. Andriole Chemoprevention of Prostate Cancer ASCO Educational Book, January 1, 2009; 2009(1): 62 - 64. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J. Theve, Y. Feng, K. Taghizadeh, K. S. Cormier, D. R. Bell, J. G. Fox, and A. B. Rogers Sex Hormone Influence on Hepatitis in Young Male A/JCr Mice Infected with Helicobacter hepaticus Infect. Immun., September 1, 2008; 76(9): 4071 - 4078. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Canguven and A. L. Burnett The Effect of 5 {alpha}-Reductase Inhibitors on Erectile Function J Androl, September 1, 2008; 29(5): 514 - 523. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K. Amory, T. F. Kalhorn, and S. T. Page Pharmacokinetics and Pharmacodynamics of Oral Testosterone Enanthate Plus Dutasteride for 4 Weeks in Normal Men: Implications for Male Hormonal Contraception J Androl, May 1, 2008; 29(3): 260 - 271. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. K. Amory, C. Wang, R. S. Swerdloff, B. D. Anawalt, A. M. Matsumoto, W. J. Bremner, S. E. Walker, L. J. Haberer, and R. V. Clark The Effect of 5{alpha}-Reductase Inhibition with Dutasteride and Finasteride on Semen Parameters and Serum Hormones in Healthy Men J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1659 - 1665. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. T. Page, D. W. Lin, E. A. Mostaghel, D. L. Hess, L. D. True, J. K. Amory, P. S. Nelson, A. M. Matsumoto, and W. J. Bremner Persistent Intraprostatic Androgen Concentrations after Medical Castration in Healthy Men J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 3850 - 3856. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. P Wiebe Progesterone metabolites in breast cancer. Endocr. Relat. Cancer, September 1, 2006; 13(3): 717 - 738. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Xu, S. L. Dalrymple, R. E. Becker, S. R. Denmeade, and J. T. Isaacs Pharmacologic Basis for the Enhanced Efficacy of Dutasteride against Prostatic Cancers. Clin. Cancer Res., July 1, 2006; 12(13): 4072 - 4079. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. R Dolder Dutasteride: A Dual 5-{alpha} Reductase Inhibitor for the Treatment of Symptomatic Benign Prostatic Hyperplasia Ann. Pharmacother., April 1, 2006; 40(4): 658 - 665. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K. Amory, S. T. Page, and W. J. Bremner Oral Testosterone in Oil: Pharmacokinetic Effects of 5{alpha} Reduction by Finasteride or Dutasteride and Food Intake in Men J Androl, January 1, 2006; 27(1): 72 - 78. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. L. Matthiesson, P. G. Stanton, L. O'Donnell, S. J. Meachem, J. K. Amory, R. Berger, W. J. Bremner, and R. I. McLachlan Effects of Testosterone and Levonorgestrel Combined with a 5{alpha}-Reductase Inhibitor or Gonadotropin-Releasing Hormone Antagonist on Spermatogenesis and Intratesticular Steroid Levels in Normal Men J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5647 - 5655. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Iranmanesh and J. D. Veldhuis Combined Inhibition of Types I and II 5 {alpha}-Reductase Selectively Augments the Basal (Nonpulsatile) Mode of Testosterone Secretion in Young Men J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 4232 - 4237. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Makridakis and J. K V Reichardt Pharmacogenetic analysis of human steroid 5{alpha} reductase type II: comparison of finasteride and dutasteride J. Mol. Endocrinol., June 1, 2005; 34(3): 617 - 623. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. L. Matthiesson, J. K. Amory, R. Berger, A. Ugoni, R. I. McLachlan, and W. J. Bremner Novel Male Hormonal Contraceptive Combinations: The Hormonal and Spermatogenic Effects of Testosterone and Levonorgestrel Combined with a 5{alpha}-Reductase Inhibitor or Gonadotropin-Releasing Hormone Antagonist J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 91 - 97. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
