Avorna Mechanism of Action

Pharmacotherapeutic group: testosterone-5-alpha-reductase inhibitors. ATC code: G04C B02.
Pharmacology: Pharmacodynamics: Mechanism of action: Dutasteride is a dual inhibitor of 5-alpha reductase. It inhibits both type 1 and type 2, 5-alpha reductase isoenzymes, which are responsible for the conversion of testosterone to dihydrotestosterone (DHT). DHT is the androgen primarily responsible for hyperplasia of glandular prostatic tissue.
Effects on DHT/Testosterone: The maximum effect of daily doses of AVORNA on the reduction on DHT is dose-dependent and is observed within 1 to 2 weeks. After 1 week and 2 weeks of daily dosing of AVORNA 0.5 mg, median serum DHT concentrations were reduced by 85% and 90%, respectively.
In BPH patients treated with 0.5 mg of dutasteride daily, the median decrease in serum DHT was 94% at 1 year and 93% at 2 years and the median increase in serum testosterone was 19% at both 1 and 2 years. This is an expected consequence of 5-alpha reductase inhibition and did not result in any known adverse events.
Effect on Prostate Volume: Significant reductions in prostate volume have been detected as early as one month after initiation of treatment and reductions continued through Month 24 (p<0.001). AVORNA led to a mean reduction of total prostate volume of 23.6% (from 54.9 mL at baseline to 42.1 mL) at Month 12 compared with a mean reduction of 0.5% (from 54.0 mL to 53.7 mL) in the placebo group. Significant (p<0.001) reductions also occurred in prostate transitional zone volume as early as one month continuing through Month 24, with a mean reduction in prostate transitional zone volume of 17.8% (from 26.8 mL at baseline to 21.4 mL) in the AVORNA group compared to a mean increase of 7.9% (from 26.8 mL to 27.5 mL) in the placebo group at Month 12. The reduction of the prostate volume seen during the first 2 years of double-blind treatment was maintained during an additional 2 years of open-label extension studies. Reduction of the size of the prostate leads to improvement of symptoms and a decreased risk for AUR and BPH-related surgery.
Pharmacokinetics: Absorption: Following administration of a single 0.5 mg dose, peak serum concentrations of dutasteride occur within 1 to 3 hours. The absolute bioavailability in man is approximately 60% relative to a 2 hour intravenous infusion. The bioavailability of dutasteride is not affected by food.
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 proteins (>99.5%).
Following daily dosing, dutasteride serum concentrations achieve 65% of steady state concentration after 1 month and approximately 90% after 3 months. Steady state serum concentrations (Css) of approximately 40 ng/mL are achieved after 6 months of dosing 0.5 mg once a day. Similarly to serum, dutasteride concentrations in semen achieved steady state at 6 months. After 52 weeks of therapy, semen dutasteride concentrations averaged 3.4 ng/mL (range 0.4 to 14 ng/mL). Dutasteride partitioning from serum into semen averaged 11.5%.
Metabolism: In vitro, dutasteride is metabolised by the human cytochrome P450 isoenzyme CYP3A4 to two minor monohydroxylated metabolites, but it is not metabolized by CYP1A2, CY2A6, CYP2E1, CYP2C8, CYP2C9, CYP2C19, CYP2B6, or CYP2D6.
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 five human serum metabolites of dutasteride have been detected in rat serum, however the stereochemistry of the hydroxyl additions at the 6 and 15 positions in the human and rat metabolites is not known.
Elimination: Dutasteride is extensively metabolised. Following oral dosing of dutasteride 0.5 mg/day to steady state in humans, 1.0% to 15.4% (mean of 5.4%) of the administered dose is excreted as dutasteride in the faeces. The remainder is excreted in the faeces as 4 major metabolites comprising 39%, 21%, 7%, and 7% each of drug-related material and 6 minor metabolites (less than 5% each).
Only trace amounts of unchanged dutasteride (less than 0.1% of the dose) are detected in human urine.
At therapeutic concentrations, the terminal half-life of dutasteride is 3 to 5 weeks.
Serum concentrations remain detectable (greater than 0.1 ng/mL) for up to 4 to 6 months after discontinuation of treatment.
Linearity/non-linearity: Dutasteride pharmacokinetics can be described as first order absorption process and two parallel elimination pathways, one saturable (concentration-dependent) and one non-saturable (concentration-independent).
At low serum concentrations (less than 3 ng/mL), dutasteride is cleared rapidly by both the concentration-dependent and concentration-independent elimination pathways. Single doses of 5 mg or less showed evidence of rapid clearance and a short half-life of 3 to 9 days.
At serum concentrations greater than 3 ng/mL, dutasteride is cleared slowly (0.35 to 0.58 L/h) primarily by linear, non-saturable elimination with terminal half-life of 3 to 5 weeks. At therapeutic concentrations, following repeat dosing of 0.5 mg/day, the slower clearance dominates and the total clearance is linear and concentration-independent.
Elderly: Dutasteride pharmacokinetics and pharmacodynamics 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. Exposure of dutasteride, represented by AUC and Cmax values, was not statistically different when comparing age groups. Half-life was not statistically different when comparing the 50 to 69 year old group to the greater than 70 years old group, which encompasses the age of most men with BPH. No differences in drug effect as measured by DHT reduction were observed between age groups. Results indicated that no dutasteride dose-adjustment based on age is necessary.
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 on the pharmacokinetics of dutasteride in hepatic impairment has not been studied.