PHARMACOKINETICS AND PHARMACODYNAMICS

The pharmacokinetics of dutasteide have been extensively studied in helthy volunteeres as well as in patients with BPH. (24) The pharmacokinetics of finasteride have been evaluated in healthy volunteers (45-60 years old nd > 70 years old) and patients with renal dysfunction (21). The phormacokinetics of neither drug have been evaluated in patients with hepatic dysfunction.

Major pharmacokinetic and pharmacodynamic parameteres for these drugs are summarized in Table 1. These data are not from direct comparative trials.

Both finasteride and dutasteride are rapidly ablsorbed. Mean bioavailability values are approximately 60%, and administration with food does not significantly affect the bioavailability of either agent. The volume of distribution for both drugs is large, but it is much larger for dutasteride (Table 1). Both drugs are highly bound to plasma proteins. For both drugs, small amounts of the drug are found in the semen but neigher drug accumulates in seminal fluid (14,15,21). the amount of dutasteride partitioning into serum after chronic dosing is 11.5% (14(.

With chronic dosing, both drugs accumulate slowly to steady-state concentrations, althoughserum DHT concentration reductions occur rapidly (14,15). Following daily dosing with dutasteride 0.5mg, 65% and approximately 90% of steady-state serum concentrations are achieved after 1 and 3 months, respectively (14), and steady-state serum concentrations are completely achieved within 6 months (24). The time for steady-state concentrations to be achieved is not known for finasteride, but is longer than 17 days (15,21).

In vitro plasma protein binding studies have been conducted with dutasteride. In these studies, no protein binding displacement occurred with other highly bound drugs such as phenytoin, warfarin or diazepam. (25)

Both finasteride and dutasteride undergo extensive hepatic metabolism primarily via the cytochrome P450 3A4 (CYP 3A4) isoenzyme system (14,15). Dutasteride is also partly metabolized by the CYP 3A5 pathway (26). Dutasteride is not metabolized in vitro by human cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. Additionally, dutasteride does not inhibit the in vitro metabolism of model substrates for the major human cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at a concentration of 1000ng/ml, 25 times greater than steady-state serum concentrations in humans (26).

No clinically meaningful drug interactions have been observed with either drug. Both drugs have a wide margin of safety and have been administered in doses of >10 times normal recommended doses for 10 to 12 weeks without an increase in adverse events. (14,20) Dutasteride has been safely administered at doses of 40 mg (80 times greater than the therapeutic 0.5mg dose) daily for 7 days and 5mg (10 times greater than the therapeutic 0.5mg dose) daily for 6 months witohout significant safety concerns (14). Dutasteride in doses up to 5mg daily has been shown to have no effect on the QTc interval (27). Consequently, no dosage adjustment is warranted when dutasteride is given eonccomitantly wit hCYP3A4 inhibitors. (28). Due to the lack of drug interactionstudies, the Prescribing Information includes the following precautionary statemetn "Because of the potentioal for durg-drug interactions, care should be taken when administering dutasteride to patients taking potent!, chronic CYP3A4 enzyme inhibitors (e.g., ritonavir)".

The elimination half-life of dutasteride is 3-5 weeks, much longer than that of finasteride. dollowo\ing discontinuation of dutasteride, serum DHT concentrations retutn to witning 20% of baseline withing 4 months (24). Although the elimination of half-life of finasteide is 6-8 hours, the rate of return to within 20% of baseline DHT concentrations after discontinuation of therapy takes 4 weeks(18) due to the slow rate of turnover of the type 2 isoenzyme-finateride complex, which has a half-life of approximately 30 hours (15,17).

Table 1: Pharmacokinetic Parameters for Dutasteride and Finasteride

CLINICAL EFFICACY 

Finasteride

Finasteride was approved by the FDA for ther treatment of BPH in 1992. Early trials with finasteride that enrolled patients with symptoms of BPH in 1992. Early trials with finasteride that enrolled patients with symptoms of BPH regardless of prstate size demonstrated vfarioable improvements in BPH symptoms (reviewedin reference 29). Boyle et al. (29) subsequently conducted a meta-analysis of 6 previous trials of at least 1 year duration and evaluated the pooled results by smaller and larter prostate size.. Baseline prostate volume was a kdey predictor of outcomes, accounting for approximately 80 of varioationin treatment effects noted between theese studeies. the fiffernences in the magnitude of improbement between finasteride and placebo for symptoms and peak urinary flow rates (Qmax) was significant ofr ment with a baseline PV > 40cc, suggesting that finasteride was benevicialin patients with enlarged prostaes ( > 40cc). (29)

Finasteride was initially evaluated in patients with symptoms of BPH and enlarged prostates cy digital rectal exam (DRE) in two, oney-year placebo ocontrolled double-blind trials each with a 5-year oopen-label extension(15). It was further evaluated in the Proscar Long-term Efficacy and Safety Study (PLESS), the largest trial of finasterideperformed thus far. IN PLESS, a total of 3040 men with symptomatic BPH and an enlarged prostate on DRE were randomized to receive finasteride 5mg daily (n=1524) or placebo (n=1516) for 4 years. Of the 3040 men, 1883 completed the 4-year study (1000 finasteride, 883 placebo). The primary endpoint of the study was the effect of mecication on symptom score as measured by the change from baseline American Urological Association Symptom Index (AUA-SI) score. Prostate volume was measured in a subset of 312 patients from the study (157 in finasteride group and 155 in placebo) and was measured by magnetic resonance imaging (MRI) at yearly inter!vals. (30)

Fnasteride treatment resulted in significant improvement in symptom scores and maximum urinary flow rate (Table 2). The mean prostate volume decreeased furing the first year in the finasteride group, with no further increase thereafter., while it increased continuously in patients recieving placego. At 4 years, the risk of undergoing BpH-related surgery was 55% lowerin patients receiving finasteride compared with placebo, and the risk reduction for experiencing acute urinary retention (AUR) was reduced by 57% (all ;,0.001).(30)

Table 2. Clinical endpoints in PLESS after 48 months of finasteride or placebo (30)

Drug-related sexual adverse events, gynecomastia and rash occurred more frequently in the finasteride group than in the placebo group. Most patients experienced the onset of drug-related adverse events within the first year of therapy. (30)

Dutasteride

Three essentially identical randomized, double-blind, placebo-controlled parallel clinical trials evaluated the efficacy and safety of dutasteride 0.5 mg once daily for 2 years for the treatment of BPH followed by a 2-year open-label extension. A pooled analysis of these 3 trials was prospectively planned. The trials were generally similar to those of the PLESS trial with finasteride. The mean baseline AUA-SI symptom scores and prostate volumes were relatively similar among the trials (AUA-SI: 15 and 17 units, prostate volume: 54 and 55cc for finasteride and dutasteride, respectively). However, there were some notable differences in trial design between the studies, which are noted below.

The dutasteride trials included larger number of patients (N=4325) and patients received double-blind therapy for 2 years, as compared with 4 years in PLESS. Only patients with serum PSA values > 1.5ng/mL were enrolled, while the PLESS trial enrolled patient with lower PSA values also. Both trials excluded patients with serum PSA values > 10 ng/mL. Patients were enrolled in the dutasteride trials if their prostate volume was > 30cc and all patients had serial prostate volume measurements by transrectal ultrasound (TRUS). In addition, the primary endpoint in the dutasteride trials at the 24-month timepoint was the incidence of AUR. (24)

Results of the dutasteride clinical trials are presented in Table 3, which represents intent-to-treat analyses using the last observation carried forward. At 2 years, dutasteride reduced the risk of AUR by 57% compared with placebo (p<0.001), and the risk reduction increased with time during the trial (24). The mean prostate volume decreased by 26.7% at 24 months. Reductions in prostate volume were observed at 1 month and continued throughout the 24-month period. In addition, at 2 years, dutasteride therapy reduced the risk of BPH-related surgical interventions by 48% (all p<0.001). Symptom scores improved by 3 months in 1 of the 3 studies and by month 12 in the other 2 studies. (14, 24). Similar results were found when data obtained at the last visit were used, which have recently been published (31).

Table 3. Clinical endpoints in Phase III trials after 24 months of dutasteride or placebo (14)

Drug-related sexual adverse events, gynecomastia and rash occurred more frequently in the finasteride group than in the placebo group. Most patients experienced the onset of drug-related adverse events within the first year of therapy. (28, 31)

In both the finasteride and dutasteride trials, discontinuation rates were significantly higher in the placebo group as compared to the active treatment groups. (28, 30, 31)