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Duagen

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Duagen

CLINICAL PHARMACOLOGY

Pharmacodynamics

Mechanism of Action: Dutasteride inhibits the conversion of testosterone to 5α-dihydrotestosterone (DHT). DHT is the androgen primarily responsible for the initial development and subsequent enlargement of the prostate gland. Testosterone is converted to DHT by the enzyme 5α-reductase, which exists as 2 isoforms, type 1 and type 2. The type 2 isoenzyme is primarily active in the reproductive tissues while the type 1 isoenzyme is also responsible for testosterone conversion in the skin and liver.

Dutasteride is a competitive and specific inhibitor of both type 1 and type 2 5α-reductase isoenzymes, with which it forms a stable enzyme complex. Dissociation from this complex has been evaluated under in vitro and in vivo conditions and is extremely slow. Dutasteride does not bind to the human androgen receptor.

Effect on DHT and Testosterone: The maximum effect of daily doses of dutasteride on the reduction of DHT is dose dependent and is observed within 1 to 2 weeks. After 1 and 2 weeks of daily dosing with dutasteride 0.5 mg, median serum DHT concentrations were reduced by 85% and 90%, respectively. In patients with BPH treated with dutasteride 0.5 ing/day for 1 year, the median decrease in serum DHT was 94%. The median increase in serum testosterone was 19% but remained within the physiologic range.

In BPH patients treated with 5 mg/day of dutasteride or placebo for up to 12 weeks prior to transurethral resection of the prostate, mean DHT concentrations in prostatic tissue were significantly lower in the dutasteride group compared with placebo (784 and 5793 pg/g, respectively, p<0.001). Mean prostatic tissue concentrations of testosterone were significantly higher in the dutasteride group compared with placebo (2073 and 93 pg/g, respectively, p<0.00]).

Adult males with genetically inherited type 2 5α-reductase deficiency also have decreased DHT levels. These 5α-reductase deficient males have a small prostate gland throughout life and do not develop BPH. Except for the associated urogenital defects present at birth, no other clinical abnormalities related to 5α-reductase deficiency have been observed in these individuals.

Other Effects: Plasma lipid panel and bone mineral density were evaluated following 52 weeks of dutasteride 0.5 mg once daily in healthy volunteers. There was no change in bone mineral density as measured by dual energy x-ray absorptiometry (DEXA) compared with either placebo or baseline. In addition, the plasma lipid profile (i.e., total cholesterol, low density lipoproteins, high density lipoproteins, and triglycerides) was unaffected by dutasteride. No clinically significant changes in adrenal hormone responses to ACTH stimulation were observed in a subset population (n = 13) of the one-year healthy volunteer study.

Pharmacokinetics:

Absorption: Following administration of a single 0.5-mg dose of a soft gelatin capsule, time to peak serum concentrations (Tmax) of dutasteride occurs within 2 to 3 hours. Absolute bioavailability in five healthy subjects is approximately 60% (range 40% to 94%). When the drug is administered with food, the maximum serum concentrations were reduced by 10% to 15%. This reduction is of no clinical significance.

Distribution: Pharmacokinetic data following single and repeat oral doses show that dutasteride has a large volume of distribution (300 to 500 L). Dutasteride is highly bound to plasma albumin (99.0%) and alpha-1 acid glycoprotein (96.6%).

In a study of healthy subjects (n = 26) receiving dutasteride 0.5 mg/day for 12 months, semen dutasteride concentrations averaged 3.4 ng/mL (range 0.4 to 14 ng/mL) at 12 months and, similar to serum, achieved steady-state concentrations at 6 months. On average, at 12 months, 11.5% of serum dutasteride concentrations partitioned into semen.

Metabolism and Elimination: Dutasteride is extensively metabolized in humans. While not all metabolic pathways have been identified, in vitro studies showed that dutasteride is metabolized by the CYP3A4 isoenzyme to 2 minor mono-hydroxylated metabolites. Dutasteride is not metabolized in vitro by human cytochrome P450 isoenzymes CYP1A2, CYP2C9, CYP2C19, and CYP2D6 at 2000 ng/mL (50-fold greater than steady-state serum concentrations). In human serum, following dosing to steady state, unchanged dutasteride, 3 major metabolites (4'-hydroxydutasteride, 1,2-dihydrodutasteride, and 6-hydroxydutasteride) and 2 minor metabolites (6,4'-dihydroxydutasteride and 15-hydroxydutasteride), as assessed by mass spectrometric response, have been detected. The absolute stereochemistry of the hydroxyl additions in the 6 and 15 positions is not known, hi vitro, 4'-hydroxydutasteride and 1,2-dihydrodutasteride metabolites are much less potent than dutasteride against both isoforms of human 5AR. The activity of 6p-hydroxydutasteride is comparable to that of dutasteride.

Dutasteride and its metabolites were excreted mainly in feces. As a percent of dose, there was approximately 5% unchanged dutasteride (-1% to -15%) and 40% as dutasteride-related metabolites (~ 2% to ~90%). Only trace amounts of unchanged dutasteride were found in urine (<1%). Therefore. on average, the dose unaccounted for approximated 55% (range 5% to 97%).

The terminal elimination half-life of dutasteride is approximately 5 weeks at steady state. The average steady-state serum dutasteride concentration was 40 ng/mL following 0.5 mg/day for 1 year. Following daily dosing, dutasteride serum concentrations achieve 65% of steady-state concentration after 1 month and approximately 90% after 3 months. Due to the long half-life of dutasteride, serum concentrations remain detectable (greater than 0.1 ng/mL) for up to 4 to 6 months after discontinuation of treatment.

Special Populations: Pediatric: Dutasteride pharmacokinetics have not been investigated in subjects less than 18 years of age.

Geriatric: No dose adjustment is necessary in the elderly. The pharmacokinetics and pharmacodynamics of dutasteride were evaluated in 36 healthy male subjects between the ages of 24 and 87 years following administration of a single 5-mg dose of dutasteride. In this single-dose study, dutasteride half-life increased with age (approximately 170 hours in men 20 to 49 years of age, approximately 260 hours in men 50 to 69 years of age, and approximately 300 hours in men over 70 years of age). Of 2166 men treated with dutasteride in the 3 pivotal studies. 60% were age 65 and over and ] 5% were age 75 and over. No overall differences in safety or efficacy were observed between these patients and younger patients.

Gender: Duagen (dutasteride) is not indicated for use in women (see WARNINGS and PRECAUTIONS). The pharmacokinetics of dutasteride in women have not been studied.

Race: The effect of race on dutasteride pharmacokinetics has not been studied.

Renal Impairment: The effect of renal impairment on dutasteride pharmacokinetics has not been studied. However, less than 0.1% of a steady-state 0.5-mg dose of dutasteride is recovered in human urine, so no adjustment in dosage is anticipated for patients with renal impairment.

Hepatic Impairment: The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Because dutasteride is extensively metabolized, exposure could be higher in hepatically impaired patients (see PRECAUTIONS: Use in hepatic impairment).

Drug Interactions:

In vitro drug metabolism studies reveal that dutasteride is metabolized by human cytochrome P450 isoenzyme CYP3A4. In a human mass balance analysis (n = 8), dutasteride was extensively metabolized. Less than 20% of the dose was excreted unchanged in the feces. No clinical drug interaction studies have been performed to evaluate the impact of CYP3A4 enzyme inhibitors on dutasteride pharmacokinetics. However, based on the in vitro data, blood concentrations of dutasteride may increase in the presence of inhibitors of CYP3A4 such as ritonavir, ketoconazole, verapamil, diltiazem, cimetidine, and ciprofloxacin. Dutasteride is not metabolized in vitro by human cytochrome P450 isoenzymes CYP1A2, CYP2C9, CYP2C19, and CYP2D6 at 2000 ng/mL (50-fold greater than steady-state serum concentrations),

Clinical drug interaction studies have shown no pharmacokinetic or pharmacodynamic interactions between dutasteride and tamsulosin, terazosin, warfarin, digoxin, and cholestyramine (see PRECAUTIONS: Drug Interactions)

Dutasteride does not inhibit the in vitro metabolism of model substrates for ihe major human cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at a concentration of 1000 ng/mL, 25 times greater than steady-state serum concentrations in humans.

CLINICAL STUDIES: Dutasteride 0.5 mg/day (n =2166) or placebo (n = 2158) was evaluated in male subjects with BPH in three 2-year multicenter, placebo-controlled, double-blind studies, each with 2-year open-label extensions. Data from the first 12 months of the trials are presented. More than 90% of the study population was Caucasian. Subjects were at least 50 years of age with BPH diagnosed by medical history and physical examination, including enlarged prostate (>30 cc) and BPH symptoms that were moderate to severe according to the American Urological Association Symptom Index (AUA-SI). Most of the 4324 subjects randomly assigned to receive either dutasteride or placebo completed the first full year of treatment (82% and 81%, respectively).

Effect on Symptom Scores: Symptoms were quantified using the AUA-SI, a questionnaire that evaluates urinary symptoms (incomplete emptying, frequency, intermittency, urgency, weak stream, straining, and nocturia) by rating on a 0 to 5 scale for a total possible score of 35. The baseline AUA-SI score across the three studies was approximately 17 units in both treatment groups.

Subjects receiving dutasteride achieved statistically significant improvement in symptoms versus placebo by Month 3 in one study, and by Month 12 in the other two pivotal studies. At Month 12, the mean decrease from baseline in AUA-SI symptom scores across the three studies pooled was -3.3 units for dutasteride and -2.1 units for placebo with a mean difference between the two treatment groups of-1.2 (range, -].] to -1.5 units in each of the three studies, p<0.001) and was consistent across the three studies. The differences between active treatment and placebo were larger in the sub-population of subjects with baseline prostate volumes of at least 40 cc.

Effect on Prostate Volume: A prostate volume of at least 30 cc measured by transrectal ultrasound was required for study entry. The mean prostate volume at study entry was approximately 54 cc.

Statistically significant differences (dutasteride versus placebo) were noted at the earliest post-treatment prostate volume measurement in each study (Month 1, Month 3, or Month 6) and continued through Month 12. At Month 12, the mean percent decrease in prostate volume across the three studies pooled was -22.2% for dutasteride and -0.5% for placebo; the mean difference (dutasteride minus placebo) was -21.7% (range, -21.1% to -22.5% in each of the three studies, p0.00l).

Effect on Maximum Urine Flow Rate: A mean peak urine flow rate (Qmax) of <15 mL/sec was required for study entry. Baseline Qmax was approximately 10 mL/sec at baseline across the three pivotal studies.

Differences between the two groups were statistically significant from baseline at Month 3 in all three studies and were maintained through Month 12. At Month 12, the mean increase in Qmax across the three studies pooled was 1.6 mL/sec for dutasteride and 0.7 mL/sec for placebo; the mean difference (dutasteride minus placebo) was 0.9 mL/sec (range, 0.7 to 1.1 mL/sec in each of the three studies, p<0.001).

Summary of Clinical Studies: The data from these studies showed improvement in BPH-related symptoms, decreased prostate volume, and increased maximum urinary flow rates with dutasteride treatment.

Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.

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