Tamduet Mechanism of Action

Pharmacotherapeutic Group: Alpha-adrenoreceptor antagonist.
Pharmacology: Pharmacological Action: Dutasteride + Tamsulosin HCl is a combination of two drugs: Dutasteride, a dual 5α-reductase inhibitor (5 ARI), and Tamsulosin hydrochloride, an antagonist of α_1a and α_1d adrenoreceptors. These drugs have complementary mechanisms of action that rapidly improve symptoms, and urinary flow and reduce the risk of acute urinary retention (AUR) and the need for BPH-related surgery.
Dutasteride 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 prostate growth and BPH development. Tamsulosin inhibits α_1a and α_1d adrenergic receptors in the stromal prostatic smooth muscle and bladder neck. Approximately 75% of the α₁-receptors in the prostate are of the α_1a subtype.
The combination of Dutasteride and Tamsulosin improves symptoms more than either component alone. After 2 years of treatment, co-administration therapy showed a statistically significant adjusted mean improvement in symptom scores from baseline of -6.2 units.
Pharmacokinetics: Absorption: Dutasteride: Following oral administration of a single 500 mcg Dutasteride dose, the time to peak serum concentrations of Dutasteride is 1 to 3 hours. The absolute bioavailability is approximately 60%. The bioavailability of Dutasteride is not affected by food.
Tamsulosin: Tamsulosin is absorbed from the intestine and is almost completely bioavailable. Both the rate and extent of absorption of Tamsulosin are reduced when taken within 30 minutes of a meal. Uniformity of absorption can be promoted by the patient always taking Dutasteride + Tamsulosin HCl after the same meal. Tamsulosin shows dose-proportional plasma exposure. After a single dose of Tamsulosin in the fed state, plasma concentrations of Tamsulosin peak at around 6 hours and, in the steady state, which is reached by day 5 of multiple dosing, the mean steady-state C_max in patients is about two-thirds higher than that reached after a single dose. Although this was observed in elderly patients, the same finding would also be expected in younger patients.
Distribution: Dutasteride: Dutasteride has a large volume of distribution (300 to 500 L) and 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 (C_ss) of approximately 40 ng/mL are achieved after 6 months of dosing 0.5 mg once a day. Dutasteride partitioning from serum into semen averaged 11.5%.
Tamsulosin: In man, Tamsulosin is about 99% bound to plasma proteins. The volume of distribution is small (about 0.2 L/kg).
Biotransformation: Dutasteride: Dutasteride is extensively metabolized in vivo. In vitro, Dutasteride is metabolized by the cytochrome P450 3A4 and 3A5 to three monohydroxylated metabolites and one dihydroxylated metabolite. Following oral dosing of Dutasteride 500 mcg/day to steady state, 1.0% to 15.4% (mean of 5.4%) of the administered dose is excreted as unchanged Dutasteride in the feces. The remainder is excreted in the feces 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.
Tamsulosin: There is no enantiomeric bioconversion from Tamsulosin hydrochloride [R(-) isomer] to the S(+) isomer in humans. Tamsulosin hydrochloride is extensively metabolized by cytochrome P450 enzymes in the liver and less than 10% of the dose is excreted in urine unchanged. However, the pharmacokinetic profile of the metabolites in humans has not been established. In vitro results indicate that CYP3A4 and CYP2D6 are involved in the metabolism of Tamsulosin as well as some minor participation of other CYP isoenzymes. Inhibition of hepatic drug-metabolizing enzymes may lead to increased exposure to Tamsulosin. The metabolites of Tamsulosin hydrochloride undergo extensive conjugation to glucuronide or sulfate prior to renal excretion.
Elimination: Dutasteride: The elimination of dutasteride is dose-dependent. The process appears to be described by two parallel elimination pathways: one that is saturable at clinically relevant concentrations and one that is non-saturable. 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.
Following repeat dosing of 500 mcg/day at therapeutic concentrations, the slower, linear elimination pathway is dominating and the half-life is approximately 3-5 weeks.
Tamsulosin: Tamsulosin and its metabolites are mainly excreted in the urine with about 9% of a dose being present in the form of an unchanged active substance. Following intravenous or oral administration of an immediate-release formulation, the elimination half-life of Tamsulosin in plasma ranges from 5 to 7 hours. Due to the absorption rate-controlled pharmacokinetics with Tamsulosin-modified release capsules, the apparent elimination half-life of Tamsulosin in the fed state is approximately 10 hours and in the steady state in patients approximately 13 hours.