Abstract
Dutasteride, a synthetic 4-azasteroid, is a selective and competitive inhibitor of both type 1 and type 2 5-alpha-reductase isoenzymes approved for the treatment of men with symptomatic benign prostatic hyperplasia (BPH) who have an enlarged prostate. It has been demonstrated to be effective as monotherapy, or in combination with the alpha-adrenergic antagonist (α-blocker), tamsulosin, in several randomized, double-blind, placebo controlled trials and their open-label extensions. Treatment with dutasteride is generally safe and well tolerated. Dutasteride has become established in the management of men with lower urinary tract symptoms (LUTS) and reduces the risk of acute urinary retention and surgery related to BPH. Dutasteride may also have a role as a chemopreventive agent in the future as emerging evidence demonstrates a reduced risk of prostate cancer with this agent.
Introduction
The potent androgen dihydrotestosterone (DHT) is a metabolite of testosterone produced by the intracellular enzyme 5 α-reductase. DHT is critical for the development of the male external genitalia, urethra, and prostate as well as male sexual maturation at puberty. 1 Later in life, DHT has been found to be the primary androgen responsible for male pattern hair loss. 2 In addition, DHT has a pathologic role with prostatic disorders, such as benign prostatic hyperplasia (BPH). 3
There are two steroid 5 α-reductase enzymes which have been discovered, type 1 and type 2. 4 Type 1 has been reported to be located throughout the body including the liver, prostate, and skin. Type 2 is also found in extra-prostatic tissues but is predominantly located in the male genitalia and prostate. 5 Investigators have demonstrated presence of 5 α-reductase types 1 and 2 mRNA in each zone of the prostate. When compared with normal prostate tissue BPH tissue was found to have a significant increase in expression of 5 α-reductase types 1 and 2 mRNA. They also found in prostate cancer specimens higher expression of 5 α-reductase type 1 but not type 2 mRNA than in normal prostate tissue.6,7
Males born with a deficiency of the type 2 5 α-reductase enzyme have been found to have impaired masculinization of the external genitalia and a rudimentary prostate. These individuals do not develop BPH or prostate cancer and these findings ultimately led to the development and use of 5 α-reductase inhibitors for the treatment of BPH. 8 The two 5 α-reductase inhibitors currently approved for clinical use are finasteride and dutasteride.
Mechanism of Action and Pharmacokinetic Profile
Dutasteride, a synthetic 4-azasteroid, is a selective and competitive inhibitor of both type 1 and type 2 5 α-reductase isoenzymes. 5 α-reductase is responsible for the intracellular conversion of testosterone to DHT, the primary androgen critical in the initial development and subsequent growth of prostate tissue. 9 In comparison to finasteride, a specific inhibitor of type 2 5 α-reductase, dutasteride is more potent with a higher reduction in DHT concentrations at equally potent doses. 10 After treatment with dutasteride 0.5 mg daily for two weeks, DHT serum levels were decreased by 90%. 9
Dutasteride is administered orally. Following a single dose of 0.5 mg, peak serum concentrations (Tmax) are reached within two to three hours. In healthy subjects, the absolute bioavailability is 60% (range 40%–94%). Maximum serum concentrations are reduced by food, but the reduction was not determined to be clinically significant. Upon reaching systemic circulation, dutasteride is highly bound to albumin (99%) and alpha-1 acid glycoprotein (96.6%) and widely distributed throughout the central and peripheral compartments. 9
Dutasteride is extensively metabolized in the liver by the cytochrome P450 (CYP) isoenzymes CYP3A4 and CYP3A5. Two minor metabolites (6,4′-dihydroxydutasteride and 15-hydroxydutasteride) and three major metabolites (4′-hydroxydutasteride, 1,2-dihydrodutasteride, and 6-hydroxydutasteride) are identified in the human serum. Of these metabolites, only 6-beta-hydroxydutasteride maintains activity comparable to dutasteride. Dutasteride and its metabolites are mainly excreted in the feces (5% unchanged and 40% as metabolites). Less than 1% of dutasteride was found unchanged in the urine and 55% of a dose is unaccounted for. At steady state, the terminal elimination half life of dutasteride is approximately five weeks. Serum concentrations achieve 65% of steady state after daily dosing for one month and 90% after three months and remain detectable for up to four to six months after discontinuation of treatment. 9
In a single-dose study of dutasteride 0.5 mg in 36 healthy male subjects aged 24–87 years, the half life increased considerably with age. The half life lasted 170 hours in men aged 20–49 years, 260 hours in men aged 50–69 years, and 300 hours in men greater than 70 years old. No differences in safety were seen between the different age groups and no dose adjustment is currently recommended. 9
The effect of renal and hepatic impairment on dutasteride pharmacokinetics has not been studied. Since dutasteride is extensively metabolized in the liver, patients with hepatic impairment are more likely to have higher systemic exposure to the drug. However, no dose adjustment recommendations have been made for this patient population. No dose adjustments are necessary in patients with renal impairment since a minimal amount of drug is eliminated through the kidneys. 9
Dutasteride is contraindicated for the use in women of childbearing potential and during pregnancy. This population should also avoid handling the dutasteride capsule due to the potential of absorption through contact with skin. Dutasteride use is also contraindicated in pediatric patients younger than 18 years old. 9
Dutasteride for the Treatment of BPH
Lower urinary tract symptoms (LUTS) become increasingly common in aging men and have been associated with a reduction in quality of life. 11 These symptoms may be secondary to BPH and bladder outlet obstruction. 12 Autopsy studies revealed the prevalence of histologically diagnosed BPH to reach 50% by 60 years of age, then progressively rise to over 80% in men older than 80 years old. 13 The two classes of drugs available for non-surgical management of BPH are alpha-adrenergic antagonists (α-blockers) and 5 α-reductase inhibitors. While α-blockers help in relaxing the bladder neck and prostate, 5 α-reductase inhibitors act by reducing the size of the prostate gland. 14
The clinical efficacy and safety of dutasteride was evaluated in a trial of 4325 men with BPH. This was a three parallel, randomized, double-blind, placebo-controlled phase III trial of 24 months duration. Serum DHT levels were reduced from baseline by more than 90% at two years. This resulted in a risk reduction of acute urinary retention by 57 percent and surgical intervention by 48 percent when compared with placebo. Treatment with dutasteride also resulted in improved urinary flow rate, improved symptom score, and a reduction in total prostate volume by 25.7%. Side effects including decreased libido, impotence, ejaculation disorders, and gynecomastia were more frequent in patients treated with dutasteride. 12
Pooled data is also available from an open-label extension period of an additional 2 years, where all patients received dutasteride 0.5 mg daily, giving 4 years of efficacy and safety data on dutasteride.15–18 Those patients maintained on dutasteride after 24 months were found to have continuing improvements in maximal flow rate (
The combination of a 5 α-reductase inhibitor and an α-blocker is also utilized for the treatment of LUTS in men with BPH. The Combination of Avodart and Tamsulosin (CombAT) study looked at combination therapy with dutasteride and tamsulosin compared to monotherapy alone. This is an ongoing multicenter, double-blind, parallel group study, in which 4,844 men were randomized to receive dutasteride (n = 1,623), tamsulosin (n = 1,611), or combination therapy (n = 1,610). Included in the study were men 50 years or older who had an International Prostate Symptoms Score (IPSS) of 12 points or more, prostate volume ≥30 cc, and total serum PSA ≥ 1.5 ng/mL. 19
An interim two-year analysis was recently reported from the CombAT study with the primary end point being the change in IPSS from baseline. Combination therapy produced a significant reduction in IPSS compared with dutasteride starting from month three (mean decrease in IPSS from baseline starting at month three: 4.8 vs. 2.8,
Dutasteride as a Chemopreventive Agent
While 5 α-reductase inhibitors are routinely used for treatment of symptomatic BPH, there has been increasing interest for their role as potential chemopreventive agents. Given current understanding that both benign and prostate cancer cells are androgen responsive coupled with the knowledge that DHT has the most potent androgenic effect in the prostate, gives logic to exploring the use of 5 α-reductase inhibitors to reduce DHT levels in an effort to prevent prostate cancer.
21
Finasteride was evaluated as a chemopreventive agent in the Prostate Cancer Prevention Trial (PCPT). This trial showed that there was a 24.8% (95% CI, 18.6 to 30.6%,
The effect of dutasteride on the incidence of prostate cancer was investigated in the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial. This 4-year multicenter, double-blind, placebo-controlled, chemoprevention study evaluated 6729 men with 3305 men who received a dose of dutasteride at 0.5 mg daily and 3424 men in the placebo group. Those eligible were considered to be at increased risk of prostate cancer who had an elevated PSA (>2.5 ng/mL in men aged 50–60 and >3.0 ng/mL in men aged 60–75), 24 unlike the men in the PCPT considered to be at low risk of prostate cancer with a PSA ≤ 3 ng/mL. 22 Additional inclusion criteria included men with one prior negative prostate biopsy within 6 months of enrollment and men who were 50 to 75 years of age. Men enrolled in the study underwent subsequent 10-core transrectal ultrasound-guided biopsies at 2 and 4 years. To preserve the blinded nature of the study the PSA of participants in the dutasteride group was doubled, correcting for an average PSA reduction of 50% by dutasteride, and then randomly adjusted by 0.1 ng/mL assuring that final reported values were equally even and odd.21,24 The primary endpoint was biopsy detectable prostate cancer at 2 and 4 years of treatment. Other end points included gleason score, tumor volume, percent of positive biopsy cores, presence of high-grade intraepithelial neoplasia (HGPIN) or atypical acinar proliferation (ASAP), BPH-related outcomes, as well as safety and tolerability. 24
During the 4 year REDUCE study period dutasteride resulted in an overall relative risk reduction of 22.8% (CI 95%, 15.2 to 29.8%,
In the REDUCE trial, dutasteride also resulted in a reduction in lesions associated with prostate cancer with a relative risk reduction of 39.2% for HGPIN (
The Combat study, which was initially utilized to explore the use of combination therapy with dutasteride and tamsulosin compared with either monotherapy alone for men with LUTS,
19
was also used to study the effect of dutasteride on the risk of prostate cancer diagnosis. Participants were older men (≥50 years old) with a clinical diagnosis of BPH who were considered by the authors to be at above-average risk for prostate cancer with PSA level 1.5–10 ng/mL. The study was thought to reflect more of a typical clinical setting in which men were screened annually with PSA and digital rectal examination (DRE). Prostate biopsies were performed only for-cause based on the investigator's judgment such as a change in DRE, increase in PSA, or nodular areas detected on transrectal ultrasound of the prostate. There was a reduction in prostate cancer with dutasteride administration (either as monotherapy or in combination with tamsulosin) with a relative risk reduction of 40% (CI 95%,
Despite the reduced risk of prostate cancer demonstrated, the Oncologic Drugs Advisory Committee (ODAC) of the FDA voted against the use of dutasteride for chemoprevention in a recent supplemental New Drug Application (sNDA) for dutasteride. These men were defined as high-risk for prostate cancer with a previous negative prostate biopsy and elevated PSA. The panel members did not feel that there was a sufficient benefit-to-risk ratio to support the use of dutasteride in this patient population. 26 The FDA followed this with a complete response letter indicating that the sNDA could not be approved in its present form. 27
Safety and Tolerability
Clinical trials12,28–30 have shown treatment with dutasteride to be safe and well tolerated. Most adverse events experienced were not serious and decreased as therapy continued. Sexual side effects including impotence, decreased libido, gynecomastia and ejaculation disorder were most commonly seen in patients treated with dutasteride compared to placebo.12,28 In three large, randomized, double-blind placebo controlled clinical trials, sexual side effects occurred in at least one percent of patients who received dutasteride 0.5 mg daily over a two year period.12,28 Patients experienced the majority of these sexual side effects during the initial six months of dutasteride therapy. With the exception of gynecomastia, there were no significant sexual side effects seen beyond six months of treatment. At the end of four years in an open-label extension study, tolerability was maintained with less than one percent of patients withdrawing from the study due to drug-related adverse effects.29,30
The CombAT trial evaluated the safety and efficacy of the combination of dutasteride and tamsulosin. Safety and tolerability of combination therapy was consistent in comparison to the separate monotherapy treatments. The drug-related adverse events were significantly higher in the combination therapy versus the monotherapy groups (
Place in Therapy
Dutasteride was initially FDA approved as mono-therapy for the treatment of symptomatic BPH with an enlarged prostate and is now also approved to use in combination with tamsulosin for the same indication. 9 Both the European Association of Urology and the American Urological Association (AUA) agree that a trial of conservative management without medication for men with mild to moderate uncomplicated LUTS is reasonable to consider initially according to their most recent guidelines.32,33 Medical therapies for moderate to severe LUTS or for those who fail watchful waiting include α-blockers (alfuzosin, doxazosin, tamsulosin, and terazosin), 5 α-reductase inhibitors (Finasteride and dutasteride) for those with LUTS and an enlarged prostate, or a combination of an α-blocker and a 5 α-reductase inhibitor.32,33 While patients may choose surgical therapy as their first option, these treatments such as transurethral microwave heat treatment, transurethral needle ablation, transurethral resection of the prostate, and transurethral laser vaporization are typically reserved for patients with complications of BPH or patients with persistent bothersome symptoms despite maximal medical therapy. 32
One advantage of monotherapy with a 5 α-reductase inhibitor is the reduced risk of acute urinary retention or need for surgery for individuals with an enlarged prostate. 34 5 α-reductase inhibitors act by reducing the size of the prostate gland while α-blockers help in relaxing the bladder neck and prostate. 14 Minimum treatment duration of 6 to 12 months is generally needed to give time for adequate reduction in prostate size allowing for a notable improvement in symptoms. Then again, treatment with an α-blocker has a rapid onset of action and is not dependent on prostate size. 33 Treatment with 5 α-reductase inhibitors will also reduce an individual's PSA level. For example, a reduction in PSA by 59.5% has been demonstrated in those who received Dutasteride for 2 years. This knowledge has prompted suggested use of a PSA doubling factor for those men on dutasteride to help maintain the usefulness of PSA for prostate cancer detection. 35 However, some argue that doubling the PSA could potentially either overestimate or underestimate actual PSA in some patients. Given this concern a PSA increase of 0.3 ng/mL or greater from nadir was proposed as an alternative to the doubling rule as a threshold for triggering prostate biopsy. 36
The potential role of dutasteride as a chemopreventive agent is still evolving. The American Society of Clinical Oncology (ASCO)/AUA guideline on the use of 5 α-reductase inhibitors for prostate cancer chemoprevention urges physicians to inform men considering use of these agents that 5 α-reductase inhibitors reduce, but not completely eliminate, the risk of prostate cancer. 37 Patients should be made aware that there was an increased risk of high-grade prostate cancers (Gleason score 7 to 10) found in the PCPT study with finasteride. 22 There was not an increase in Gleason 7 to 10 tumors with dutasteride in the REDUCE trial, however there was an increase in Gleason 8 to 10 tumors at four years with dutasteride when compared with placebo. 24 Other key points from the ASCO/AUA guideline are that physicians should inform men of the possible but reversible side effects but also the likely improvement in LUTs with 5 α-reductase inhibitors. 37 What may be more difficult, however, is deciding if the advantages outweigh the disadvantages in addition to accounting for cost effectiveness when determining whether to utilize 5 α-reductase inhibitors or not for chemoprevention. Despite the reported risk reduction in prostate cancer, to date both finasteride and dutasteride are not yet approved for use as prostate cancer chemopreventive agents.
Conclusion
Dutasteride is a dual inhibitor of both isoforms of 5 α-reductase and is currently established as an effective and tolerable option in the management of LUTS for men with an enlarged prostate. Treatment with dutasteride will decrease the TPV as well as lower the risk of acute urinary retention and surgery related to BPH. In addition, dutasteride has been shown to reduce the risk of prostate cancer in older men considered to be at increased risk for prostate cancer with an elevated PSA. Further investigation is needed, though, to help further define the potential role of dutasteride as a chemopreventive agent.
Footnotes
Disclosures
This manuscript has been read and approved by all authors. This paper is unique and not under consideration by any other publication and has not been published elsewhere. E. David Crawford has the following disclosures: Consultant/Employee: Ferring. Lecturer: GlaxoSmithKline, Sanofi Aventis, Johnson and Johnson, Amgen. Consultant: Gtx. The authors confirm that they have permission to reproduce any copyrighted material.