Comparison of Propecia VS Avodart: Summary

SUMMARY

•  No long-term ( > 2 years) clinical trials have directly compared the efficacy and safeaty of dutasteride and finasteride. Withoug such trials, conclusions regarding the relative efficacy and safety of one agent over the other may not be made.

•  Both dutasteride and finasteride are 4-azasteriod competitive inhibitors of 5 alpha-reductase, the enzyme responsible for converting testosterone to dihydrotestosterone (DHT), which is the more potent androgen in the prostate. Dutasteride inhibits both types of isoenzymes (type 1 and 2) of 5 alpha-reductase while finasteride selectivelyinhibits the type 2 isoenzyme. both agents decrease epithelial cell size and funciton within the prostate in patients with benign prostatic hyperplasia (BPH) through an increased rate of apoptosis.

•  In clinical trials, chronic dutasteride thereapy reduces serum DHT by 93 to 94% while finasteride reduces serum DHT by approximately 70%. Reductions in intraprostatic DHT concentrations have not been directly compared between the two drugs. most trials assessing intraprostatic DHT reductions utilized doses higher than those used for the treatment of BPH.

•  In non-comparative trials, chronic therapy with either agent reduced prostate volume significantly in patients with BPH. Both agents have been shown to arrest the disease process in patients with BPH and are indicated to improve symptoms and to reduce the risk of acute urinary retention (AUR) and BPH-related surgery. Both agents increase serum testosterone concentrations by 10 to 20%. Neither drug affects bone mineral density nor serum lipid profiles.

•  The pharmacokinetics of ditasteride are somewhat different than that of finasteride. The major differences include a larger volume of distribution for dutasteide, resulting in a longer elimination half-life. both agents are metabolized by the cytochrome (CYP) P450 3A4 system to active metabolites, although dutasteride is also partly metabolized via the CYP 3A5 pathway, based on in vitro studies. No clinically meaningful drug interactions have been observed with either drug.

•  For both agents, the most frequently reported drug-related adverse events were related to sexual funciton. These included impotence, decreased libido, decreased volume of ejaculation and ejaculation disorders, and breast tenderness and/or enlargement. The onset of drug-related sexual adverse events appears to diminish with time for both drugs.

•  One clinical trial directly comparing dutasteride with finasteride was conducted in Europe. The primary endpoint was to evaluate the effect of either drug on prostate volume after 12 months of double-blind therapy. For the intent-to treat population, prostate volume was reduced from basleine in both the dutasteride and finasteride groups at month 12. dutasteide produced m\numerically but not statistically significant greater improvements in symptoms and urinary flow rates compared with finasteride. Although fewer drug-related sexual adverse events occurred in patients receiving dutasteride than finasteride, there were no significant differneces between the two drugs (17% in the dutasteride group compared with 20% in finasteride-treated patients). Whether similar results would occur with a longer clinical trial ( > 2 years) is not known.

•  A brief 3-month prospective and consecutive study was conducted to evaluate the onset of symptom relief with Avodart versus Proscar (finasteride, Merck & Co.) One hundred twenty men with symptomatic benign prostate hyperplasia (BPH) were treated with Avodart, followed by an additional 120 men treated consecutively with Proscar for 3 months in each trial. Among patients who recieved Avodart, there were significantly greater reductions in AUA-SO scores compared with Proscar in the first 3 months ( P <0.0016). Conclusion drawn from this study must be considered carefully in light of the study design.

INTRODUCTION

No long-term ( > 2 years) clinical trials have directly compared the efficacy and safety of dutasteride and finasteride. Without such trials, conclusitons regarding the relative efficacy and safety of one agent over the other may not be made. This letter describes differences and similarities between dutasteride and finasteride based on pharacologic, pharmacokinetic and pharmacodynamic effects, as well as a summary of clinical trial information and adverse events reported from these trials. One short-term direct comparative trial conducted in Europe is describedin which patients with benign prostatic hyperplasia (BPH) received either dutasteride or finasteride for 1 year of treatment.

COMPARISON OF PHARMACOLOGY

5alpha-Reductase Isoenzyme Inhibition

Both dutasteide and finasteride are 4-azasteroid inhibitors of 5 a -reductase , the enzyme responsible for converting testosterone to dihydrotestosterone (DHT) in the prostate. DHT is the primary androgen int the prostate and has a major role in the development and progression of benign prostatic hyperplasia (BPH) and other prostate diseases (1,2,3,4) as well as androgenetic alopecia (5,6).

Two isoenzymes of 5 a -reductase exist (type 1 and type 2). Type 2 is the dominant isoenzyme in genital tissues including the prostate, but is also present in the skin and liver. Type 1 5 a -reductase is also found in the skin, liver and prostate, and is the dominant form in sebaceous glands. (1,2,4). Although early studies did not observe the presence of type 1 isoenzyme in the prostate (5), more recent studies using more sensitive assays indicate that both type 1 and type 2 mRNA protein and enzymatic activity are present in prostate tissues. (7,8,9,10,11,12). In one of these studies, mRNA expression for both types 1 and 2 was slightly but significantly increased in BPH tissue when compared to the levels observed in normal prostate tissue. In cancer samples, type 1 mRNA expression was higher than in normal and hyperplastic prostate (11,12) but the level of type 2 mRNA was not statistically different from thatobserved in the normal prostate (11). In th!e liver, type 2 mRNA was expressed at levels similar to those measured in BPH tissue while type 1 mRNA expression was ten times higher. (11)

Finasteride is a competitive inhibitor of 5 a -reductase that selectively inhibits the type 2 isoenzyme, with which it forms a stable enzyme complex. this selective activity is attributed to a much lower affinity for the type 1 isoenzyme, and thus a slow rate of type 1 isoenzyme inhibition. In contrast, dutasteride is a competitive inhibitor of both forms of the enzyme, with 45-fold greater potency than finasteride against type 1 and type 2 isoenzymes at clinically used doses. this dual inhibition may potentially be beneficial in prostatic diseased that depend on androgens, since both isoenzymes are up-regulated in BPH while only the type 1 isoenzyme is up-regulated in prostate cancer, as noted above (2,1). However, whether clinical differences in the treatment of BPH occur between selective versus dual inhibitors of 5 a -reductase is not known.

Turnover from the enzyme complex is extremely slow for both agents. Neither agent possesses anti-gonadotrophic or anit-androgenec properties, and they do not bind to the androgen receptor. (1,14,15).

during the fi4rst several minths of therapy in patients with BPH, both dutrasteride and finasteride cause progressive decreases in epithelial cell size and function within the prostate, through and increased rate of apoptosis, which histologically is manifested by ductal atrophy (1,2,16,17).

Serum DHT Reduction

After chronic administration of doses recommended for the treatment of bPH, serum DHT suppression is significantly greater with dutasteride (0.5 mg daily) than that observed with finasteide (5mg daily). In clinical trials, chronic therapy with dutaseride 0.5mg daily for up to 2 years in patients with BPH resulted in median reductions in serum DHT concentrations of 94% and 93% after 1and 2 years, respectively (14). In contrast, long-term therapy with finasteride 5 mg daily for up to 4 years in patients with BPH suppressed serum DHT concentrations by appr5oximately 70% (15).

Treatment of BPH patients with either agent produces dose-dependent, rapid reductions in serum DHT concentrations (14,15). After 1 and 2 weeks of dutasteride 0.5 mg daily, median serum DHT concentrations were reduced by 85% and 90% respectively (14). With repeated daily dosing, serum DHT concentration reductions are observed within 8 hours after finasteride administration (15).

In addition to the above non-comparative data, a Phase II dose-ranging rial of dutasteride in patients with BPH (n=392) and an enlarged prostate ( > 30 cc as measured by transrectal ultrasound) directly compared various doses of dutasteide with finasteide 5 mg daily in a double-blind, placebo controlled trial. An additional follow-up phase for 4 months after patients had ended the double blind phase was included. The study was not powered to detect clinical differneces in symptoms between dutasteride and finasteride. The mean reduction in baseline DHTconcentration in patients recieving 0.5mg dutasteride daily was greater and less variable than in patients receiveing finasteride 5mg daily (94.7 + 3.3% and 70.8 + 18.3%, respectively, p<0.001). (18)

During the follow-up period (after study medication was stopped), mean DHT concentrations retruned to within 20% of their baseline values at 16 weeks in patients receiving dutasteride, compared with 4 weeks in those receiving finasteride.(18)

Intraprostatic DHT Reduction

Intraprostatic reductions in DHT have been evaluated in Phase II clinical trial in BPH patients after receiving 5mg dutasteride daily, a higher dose than the dosage used for the treatment of BPH. Patients were randomized to receive treatment with dutasteride 5mg daily or placebo for up to 12 weeks prior to transurethral resection of the prostate (TRUP). Mean DHT concentrations in prostatic tissue were significantly lower in the dutasteride group. Intraprostatic concentrations were 784 pg/g in the dutasteride group (N=24) compared with 5793 pg/g in the placebo group (n=19, p<0.001). Serum DHT concentration was reduced by a median value of 97.1%. (16)

In another Phase Ii clinical trial, patients weith clinically staged T1, T2 prostate cancer were randomized to receive treatment with high doses of dutasteride or placebo for 6-10 weeks prior to undergoing planned radical prostatectomy. Dutasteride was administered as a loading dose of 10mg daily for the initial 7 days followed by 5mg daily thereafter. Intraprostatic DHT values obtained in patients receiveing dutasteride were 2.9% of those obtained in patients receiving placebo, representing a 97.1% reduction in ccomparison with the placebo group. Serum DHT concentrations were reduced by 96.4% from baseline in patients receibing dutasteride without significantly increasing serum testosterone concentrations. The ratio of serum DHT to testosterone concentrations was also significantly less in subjects receiving dutasteride compared to placebo (>90% reduction with dutasteride compared to baseline). (19)

In a phase Ii trial, 69 patients with BPH were treated with finasteride 1 to 100 mg daily (one-fifth to 200 times the normal daily dosage) for 7-10 days prior to prostatectomy. Intraprostatic DHT concentrations for the entire range of dosed sdministered were approximately 80 lower than those in patients receiving placebo (15,20). Of the 69 patients, 12 patients recieved 5mg daily, the dosage used for the treatment of BPH. In these 12 patients, the exact values for intraprostatic DHT were not described. All dosage levels with in the finasteride griop resulted in statistically significant differences compared to values obtained in the placebo group, but not different from each other. However, the authors stated that the 100mg daily dose was more effective than the 1 and 5mg daily doses. (20) The study firation of 7 days was insufficient time for patients to have achieved steady-state dosing of the frug, since the time to reach steady-state dosing with finasteride is >ulnone 17 days (21).

In another trial, 27 men with symptomatic BPH were treated with placebo, 1mg finasteride daily or 5mg finasteride daily for 6-8 weeks prior to planned transurethral resection of the prostate (TURP). Serum and intraprostatic DHT concentrations correlated well. After 1 and 5mg daily dosing, serum DHT concentrations were reduced by 66% and 70% respectively. Intraprostatic DHT concentrations were reduced by approximately 80% and 90% respectively, in patients receiving 1 and 5 mg daily dosing compared to the mean value obtained at surgery in the placebo group. (22)

In another trial, 27 men with symptomatic BPH were treated with placebo, 1mg finasteride daily or 5mg finasteride daily for 6-8 weeks prior to planned transurethral resection of the prostate (TURP). Serum and intraprostatic DHT concentrations correlated well. After 1 and 5mg daily dosing, serum DHT concentrations were reduced by 66% and 70% respectively. Intraprostatic DHT concentrations were reduced by approximately 80% and 90% respectively, in patients receiving 1 and 5 mg daily dosing compared to the mean value obtained at surgery in the placebo group. (22)

The remaining DHT in the prostate after finasteride therapy is likely to be the result of type 1 5 a -reductase, either originating from the 30% of DHT remaining in the serum of men receiving finasteride or from intraprostatic type 1 5 a -reductase (1). The contribution of remaining DHT in the serum and the small amount of type 1 in the prostate may play a role in maintaining prostatic enlargement (2). Inhibition of both type 1 and type 2 5 a -reductase may potentially offer advantages in the treatment of BPH and other diseases that depend on DHT compared with selective inhibition of the type 2 isoenzyme alone (1,2,3,5). However, long-term direct comparative trials in patients with BPH are necessary to determine whether clinically significant differneces exist among dual and single inhibitors of the enzyme (dutasteride and finasteride, respectively).

The trials discussed above have not evaluated intraprostatic DHT concentration reductions after steady-state dosing had been achieved for either dutasteride or finasteride, and the doses evaluated were significantly higher than those approved for the treatment of BPH in both dutasteride trials and one of the finasteide trials. Intraprostaic concentration reductions achieved with doses approved for the treatment of BPH are not yet available for dutasteride.

Effect on Serum Testorsterone, Bone Density and Lipid Metabolism

Both dutasteride and finasteride increase median circulating testosterone concentration by 10-20% from baseline values, but concentrations remained within normal physiologic limits. In addition, neither agent causes significant changes in bone density or lipid metabolism. (14,15)

Effect on Serum PSA Values

Both agents reduce serum PSA values to similar extents. Dutasteride reduces total serum PSA concentration by approximately 40% following 3 months of treatment and approximately 50% following 6,12,and 24 months of treatment (14). This decrease is predictable over the entire range of PSA values, although it may vary in individual patients. However, since the ratio of free to total PSA is not significantly altered (23), PSA may still be used as a screening tool for the detection of prostate cancer. To interpret an isolated PSA value in a man treated with either agent for 6 months or more, the PSA value should be doubled for comparison with normal values in untreated men.(14,15)