Source: Health Products Regulatory Authority (ZA) Publisher: Zydus Healthcare SA (Pty) Ltd, Southdowns Office Park, Building B, Ground Floor, 22 Karee Street, Centurion, Pretoria 0157
Pharmacological classification: A 21.12. Hormone inhibitors
Dutasteride is a dual inhibitor of 5α-reductase isoenzymes. Dutasteride reduces circulating levels of dihydrotestosterone (DHT) by inhibiting both type 1 and type 2 5α-reductase isoenzymes, which are responsible for the conversion of testosterone to DHT. DHT is the androgen mainly responsible for hyperplasia of glandular prostatic tissue.
The maximum effect of daily doses of ZEDRAST on the reduction on DHT is dose dependent and is observed within 1–2 weeks. After 1 week and 2 weeks of daily dosing of ZEDRAST 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 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 unexpected consequence of 5α-reductase inhibition and did not result in any known adverse events.
Dutasteride has no clinically significant effect on other androgens, hormones, thyroid stimulating hormone, thyroxine, total cholesterol, low density lipoprotein, high density lipoprotein, triglycerides, bone metabolism or bone density.
Peak serum concentration occurs within 1–3 hours, following oral administration of a single 0,5 mg dutasteride dose. The absolute bioavailability is approximately 60%. Concomitant food administration has no effect on the oral bioavailability of dutasteride.
Dutasteride is highly bound to plasma proteins (>99,5%) and has a large volume of distribution (300–500 L). Serum concentrations achieve 65% of steady state concentrations after 1 month, and approximately 90% after 3 months following daily dosing with dutasteride. After 6 months of 0,5 mg dutasteride taken daily, steady state serum concentrations of approximately 40 ng/mL are achieved. Dutasteride can be detected in semen (see section 4.6) and achieved steady state after 6 months. Dutasteride partitioning from serum into semen averaged at 11,5%.
In vitro, dutasteride is metabolised by the human cytochrome P450 enzyme CYP450-3A4 to two minor monohydroxylated metabolites.
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).
Dutasteride is extensively metabolised. Following oral dosing of dutasteride 0,5 mg/day to steady state in humans, 1,0% – 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 medicine-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 3–5 weeks. Serum concentrations remain detectable (greater than 0,1 ng/mL) for up to 4–6 months after discontinuation of treatment.
Dutasteride pharmacokinetics and pharmacodynamics were evaluated in 36 healthy male subjects between ages of 24 and 87 years following administration of a single 5 mg dose of dutasteride. Exposure of dutasteride, represented by AUC and Cmax value, was not statistically different when comparing age groups. Results indicated that no dutasteride dose adjustment based on age is necessary.
The effect of renal impairment on the 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.
The effect on the pharmacokinetics of dutasteride in hepatic impairment has not been studied (see section 4.4).
No further information of relevance available.
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