Uriflo-D Mechanism of Action

Pharmacotherapeutic group: Alpha-adrenoreceptor antagonists. ATC code: G04CA52.
Pharmacology: Pharmacodynamics: Dutasteride-tamsulosin is a combination of two drugs: dutasteride, a dual 5 α-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, 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 α1a and α1d 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.
Pharmacokinetics: Bioequivalence was demonstrated between dutasteride-tamsulosin and concomitant dosing with separate dutasteride and tamsulosin capsules.
The single dose bioequivalence study was performed in both the fasted and fed states. A 30% reduction in Cmax was observed for the tamsulosin component of dutasteride-tamsulosin in the fed state compared to the fasted state. Food had no effect on AUC of tamsulosin.
Absorption: Dutasteride: Following oral administration of a single 0.5 mg 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 Uriflo-D 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 Cmax 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 metabolised in vivo. In vitro, dutasteride is metabolised by the cytochrome P450 3A4 and 3A5 to three monohydroxylated metabolites and one dihydroxylated metabolite.
Following oral dosing of dutasteride 0.5 mg/day to steady state, 1.0% to 15.4% (mean of 5.4%) of the administered dose is excreted as unchanged 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.
Tamsulosin: There is no enantiomeric bioconversion from tamsulosin hydrochloride [R(-) isomer] to the S(+) isomer in humans. Tamsulosin hydrochloride is extensively metabolised 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 metabolism of tamsulosin as well as some minor participation of other CYP isoenzymes. Inhibition of hepatic drug metabolising 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 and the process appears to be described by two elimination pathways in parallel, 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.
At therapeutic concentrations, following repeat dosing of 0.5 mg/day, the slower, linear elimination pathway is dominating and the half-life is approx. 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 unchanged active substance.
Following intravenous or oral administration of an immediate-release formulation, the elimination half life of tamsulosin in plasma range 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.
Elderly: Dutasteride: Dutasteride pharmacokinetics 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. No significant influence of age was seen on the exposure of dutasteride but the half-life was shorter in men under 50 years of age. Half-life was not statistically different when comparing the 50-69 year old group to the greater than 70 years old.
Tamsulosin: Cross-study comparison of tamsulosin hydrochloride overall exposure (AUC) and half-life indicate that the pharmacokinetic disposition of tamsulosin hydrochloride may be slightly prolonged in elderly males compared to young, healthy male volunteers. Intrinsic clearance is independent of tamsulosin hydrochloride binding to AAG, but diminishes with age, resulting in a 40% overall higher exposure (AUC) in subjects of age 55 to 75 years compared to subjects of age 20 to 32 years.
Renal impairment: Dutasteride: 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 clinically significant increase of the dutasteride plasma concentrations is anticipated for patients with renal impairment.
Tamsulosin: The pharmacokinetics of tamsulosin hydrochloride have been compared in 6 subjects with mild-moderate (30 ≤ CL_cr < 70 mL/min/1.73m²) or moderate-severe (10 ≤ CL_cr < 30 mL/min/1.73m²) renal impairment and 6 normal subjects (CL_cr > 90 mL/min/1.73m²). While a change in the overall plasma concentration of tamsulosin hydrochloride was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin hydrochloride, as well as the intrinsic clearance, remained relatively constant. Therefore, patients with renal impairment do not require an adjustment in tamsulosin hydrochloride capsules dosing. However, patients with endstage renal disease (CL_cr < 10 mL/min/1.73m²) have not been studied.
Hepatic impairment: Dutasteride: The effect on the pharmacokinetics of dutasteride in hepatic impairment has not been studied. Because dutasteride is eliminated mainly through metabolism the plasma levels of dutasteride are expected to be elevated in these patients and the half-life of dutasteride be prolonged.
Tamsulosin: The pharmacokinetics of tamsulosin hydrochloride have been compared in 8 subjects with moderate hepatic dysfunction (Child-Pugh's classification: Grades A and B) and 8 normal subjects. While a change in the overall plasma concentration of tamsulosin hydrochloride was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin hydrochloride does not change significantly with only a modest (32%) change in intrinsic clearance of unbound tamsulosin hydrochloride. Therefore, patients with moderate hepatic dysfunction do not require an adjustment in tamsulosin hydrochloride dosage. Tamsulosin hydrochloride has not been studied in patients with severe hepatic dysfunction.