Dutasteride Pharmacology
Dutasteride Mechanism of Action
Dutasteride inhibits the conversion of testosterone to 5-alpha-dihydrotestosterone (DHT). DHT is the androgen primarily responsible for the initial development and subsequent enlargement of the prostate gland, and one of the primary causes of hair loss in men. Testosterone is converted to DHT by the enzyme 5-alpha-reductase, which exists as two isoforms (Type 1 5AR and Type 2 5AR). 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 5-alpha-reductase isoenzymes, with which it forms a stable enzyme complex. Dissociation from this complex is extremely slow. Dutasteride does not bind to the human androgen receptor.
Effect of Dutasteride 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 one and two 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 mg/day for one 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 (784 pg/g) compared with placebo (5793 pg/g). Mean prostatic tissue concentrations of testosterone were significantly higher in the dutasteride group (2073 pg/g) compared with placebo (93 pg/g).
Dutasteride Absorption
Following administration of a single 0.5-mg dose of a soft gelatin capsule, time to peak serum concentrations of dutasteride occurs within 2 to 3 hours. Absolute bioavailability is approximately 60% (within a range of 40% to 94%). When dutasteride is administered with food, the maximum serum concentrations were reduced by 10% to 15%, however this reduction has no clinical significance.
Dutasteride Distribution
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 subjects 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. After 12 months, 11.5% of serum dutasteride concentrations partitioned into semen.
Dutasteride Metabolism and Elimination
Dutasteride is extensively metabolized in humans. Dutasteride is metabolized by the CYP3A4 isoenzyme to 2 minor mono-hydroxylated metabolites. Dutasteride and its metabolites are excreted primarily 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 with dutasteride.
Dutasteride Effect on BPH Symptoms
Using the American Urological Association Symptom Index (AUA-SI), subjects receiving dutasteride achieved statistically significant improvement in BPH symptoms versus placebo by month 3 and by Month 12. The AUA-SI evaluates urinary symptoms including incomplete emptying, frequency, intermittency, urgency, weak stream, straining, and nocturia.
Dutasteride Effect on Prostate Volume
Statistically significant differences between dutasteride and placebo were noted at month 1 and continued through month 6 and month 12. At Month 12, the mean percent decrease in prostate volume averaged -22.2% for dutasteride compared with -0.5% for placebo. The mean difference (dutasteride minus placebo) was -21.7%.
Effect of Dutasteride on Maximum Urine Flow Rate
Differences in maximum urine flow rate between the dutasterde group and the placebo group were statistically significant from baseline at month 3 and were maintained through month 6 and month 12. At Month 12, the mean increase in maximum urine flow rate 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.
Summary of Clinical Studies of Dutasteride
The data from dutasteride studies showed improvement in BPH-related symptoms, decreased prostate volume, and increased maximum urinary flow rate with dutasteride treatment.