Source: Health Products Regulatory Authority (ZA) Revision Year: 2023 Publisher: Austell Pharmaceuticals (Pty) Ltd, 1 Sherborne Road, Parktown, JOHANNESBURG, 2193, South Africa, Tel: 0860287835, www.austell.co.za
Pharmacological Classification/Category and Class: A 21.12 Hormone inhibitors
Pharmacotherapeutic group: testosterone-5-alpha-reductase inhibitors
ATC code: G04CB02
Dutasteride is a dual inhibitor of 5α-reductase. It inhibits both type 1 and type 2, 5α-reductase isoenzymes which are responsible for the conversion of testosterone to 5α-dihydrotestosterone (DHT). DHT is the androgen primarily responsible for hyperplasia of glandular prostatic tissue.
The maximum effect of daily doses of dutasteride 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 dutasteride 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 expected 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.
Following administration of a single 0,5 mg dose, peak serum concentrations of dutasteride occur within 1-3 hours.
Absolute bioavailability in man is approximately 60%.
The bioavailability of dutasteride is not affected by food.
Pharmacokinetic data following single and 45 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%.
In vitro, dutasteride is metabolized 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 metabolized. 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.
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.
In clinical studies, exposure of dutasteride, represented by AUC and Cmax values, was not statistically different when comparing age groups of 24 and 87 years old. 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.
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 93 for patients with renal impairment.
The effect on the pharmacokinetics of dutasteride in hepatic impairment has not been studied (see section 4.4).
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