Sign Out
Pharmacology: Pharmacodynamics: Mechanism of Action: Dutasteride + Tamsulosin HCl, is a combination of two drugs with complementary mechanism of actions to improve symptoms in patients with BPH: Dutasteride, a dual 5α-reductase inhibitor (5ARI) and Tamsulosin HCl, an antagonist of α1a-adrenoreceptors.
The pharmacodynamic effects of dutasteride-tamsulosin as a fixed combination would not be expected to be different from those of dutasteride and tamsulosin co-administered as separate components.
Dutasteride: 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 5-alpha dihydrotestosterone (DHT).
Dihydrotestoterone is the androgen primarily responsible for hyperplasia of glandular prostatic tissue. It also lowers dihydrotestosterone levels, reduces prostate volume, improves lower urinary tract symptoms and urine flow and reduces and risk of AUR and BPH-related surgery.
The maximum effect of daily doses of dutasteride on the reduction of dihydrotestosterone is dose-dependent and is observed within one to two weeks. After one week and two weeks of daily dosing of dutasteride 500 mcg, median serum DHT concentrations were reduced by 85% and 90%, respectively.
In BPH patients treated with 500 mcg of dutasteride daily, the median decrease in dihydrotestosterone was 94% at one year and 93% at two years, and median increase in serum testosterone was 19% at both one and two years. This is an expected consequence of alpha-reductase inhibition and did not result in any known adverse events.
Tamsulosin: Tamsulosin inhibits α1a adrenergic receptors in the stromal prostatic smooth muscle and bladder neck. Approximately 75% of the α1-receptors in the prostate are of the α1a subtype. Tamsulosin rapidly (from one week) increases maximum urinary flow rate by reducing smooth muscle tension in the prostate and urethra, thereby relieving obstruction. It also improves the complex of irritative and obstructive symptoms in which bladder instability and tension of the smooth muscles of the lower urinary tract play an important role. Alpha-1 adrenergic blockers can reduce blood pressure by lowering peripheral resistance.
Dutasteride: The relation between long term use of Dutasteride and male breast cancer has not been established.
Pharmacokinetics: Bioequivalence was demonstrated between Dutasteride-Tamsulosin and concomitant dosing with separate Dutasteride and Tamsulosin capsules.
The single dose bioequivalence was performed in both fasted and fed states. A 30% reduction in Cmax was observed for Tamsulosin component of Dutasteride-Tamsulosin in the fed state compared to the fasted state. Food had no effect on AUC of Tamsulosin.
Absorption: Dutasteride: Administered orally in solution as a soft gelatin capsule. Following administration of a single 0.5 mg dose, peak serum concentrations of Dutasteride occur within 1 to 3 hours.
Absolute bioavailability in man is approximately 60% relative to a 2-hour intravenous infusion. The bioavailability of Dutasteride is not affected by food.
Tamsulosin: Tamsulosin HCl is absorbed from the intestine and is almost completely bioavailable.
Tamsulosin HCl exhibits linear kinetics, following single and multiple dosing, with achievement of steady state concentrations by the fifth day of once-a-day dosing. The rate of absorption of Tamsulosin HCl is reduced by recent meal. Uniformity of absorption can be promoted by the patient always taking Tamsulosin HCl approximately 30 minutes after the same time of meal each day.
Distribution: Dutasteride: Pharmacokinetic data following single and repeat oral doses show that dutasteride has large volume of distribution (300 to 500 L). Dutasteride is highly bound to plasma proteins (greater than 99.5%).
Following daily dosing, Dutasteride serum concentration achieve 65% steady state concentration after one month and approximately 90% after three months.
Steady state serum concentrations (Css) of approximately 40 nanograms/mL are achieved after six months of dosing 0.5 mg once a day. Similarly to serum, Dutasteride concentrations in semen achieved steady state at six months. After 52 weeks of therapy, semen Dutasteride concentrations averaged 3.4 nanograms/mL (range 0.4 to 14 nanograms/mL). Dutasteride partitioning from serum into semen averaged 11.5%.
Tamsulosin: The mean steady-state apparent volume of distribution of Tamsulosin HCl after intravenous administration to ten healthy male adults was 16 L, which is suggestive of distribution into extracellular fluids in the body.
Tamsulosin HCl is extensively bound to human plasma proteins (94% to 99%), primarily alpha-1 acid glycoprotein (AAG) with linear binding over a wide concentration range (20 to 600 nanograms/mL).
Biotransformation: Dutasteride: In vitro, Dutasteride is metabolised by the human cytochrome P450 isoenzyme CYP3A4 to two minor monohydroxylated metabolites, but it is not metabolised by the CYP1A2, CY2A6, CYP2E1, CYP2C8, CYP2C9, CYP2B6 or CYP2D6.
In human serum, following dosing to steady state, unchanged Dutasteride, three 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.
Tamsulosin: Tamsulosin is no enantiomeric bioconversion from Tamsulosin HCl [R(-) isomer] to the S(+) isomer in humans. Tamsulosin HCl 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 the CYP3A4 and CYP2D6 are involved in metabolism of Tamsulosin as well as some minor participation of other CYP isoenzymes. Inhibition of hepatic drug metabolizing enzymes may lead to increase exposure to Tamsulosin. The metabolites of Tamsulosin HCl undergo extensive conjugation to glucuronide or sulfate prior to renal excretion.
Elimination: Dutasteride: Dutasteride is extensively metabolised. Following oral dosing Dutasteride 500 mcg/day 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 four major metabolites comprising 39%, 21%, 7% each of drug-related material and six minor metabolites (less than 5% each).
Only trace amounts of unchanged Dutasteride (less than 0.1% of the dose) are detected on human urine.
At therapeutic concentrations, the terminal half-life of Dutasteride is 3 to 5 weeks.
Serum concentrations remain detectable (greater than 0.1 nanogram/mL) for up to 4 to 6 months after discontinuation of treatment.
At low serum concentrations (less than 3 nanograms/mL), Dutasteride is cleared rapidly by both the concentration-dependent and concentration-independent elimination pathways. Single doses 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 nanograms/mL, Dutasteride is cleared slowly (0.35 to 0.58 L/hr) primarily by linear, non-saturable elimination with terminal half-life of three to five weeks. At the therapeutic concentrations, the terminal half-life of Dutasteride is three to five weeks, and following repeat dosing of 500 mcg/day, the slower clearance dominates and the total clearance is linear and concentration-independent.
Tamsulosin: Tamsulosin half-life is 5 to 7 hours. Approximately 10% is excreted unchanged in urine.
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 or 69 year old group with greater than 70 year 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: Dutasteride: The effect of renal impairment on Dutasteride pharmacokinetics has not been studied. However, less than 0.1% of steady-state 500 mcg dose of Dutasteride is recovered in human urine, so no adjustment in dosage is anticipated for patients with renal impairment.
Tamsulosin: The pharmacokinetics of Tamsulosin have been compared in 6 subjects with mild-moderate (30 ≤ CrCl < 70 mL/min/1.73 m2) or moderate-severe (10 ≤ CrCl < 30 mL/min/1.73 m2) renal impairment and 6 normal subjects (CrCl < 90 mL/min/1.73 m2). While a change in the overall plasma concentration of Tamsulosin was observed as the result of altered binding to AAG, the unbound active) concentration of Tamsulosin, as well as the intrinsic clearance, remained relatively constant. Therefore, patients with renal impairment do not require an adjustment in Tamsulosin HCl capsules dosing.
Hepatic Impairment: Dutasteride: The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Because dutasteride is extensively metabolized, exposure could be higher in hepatically impaired patients.
Tamsulosin: The pharmacokinetics of tamsulosin have been compared in 8 subjects with moderate hepatic impairment (Child-Pugh classification: Grades A and B) and 8 normal subjects. While a change in the overall plasma concentration of tamsulosin was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin does not change significantly with only a modest (32%) change in intrinsic clearance of unbound tamsulosin. Therefore, patients with moderate hepatic impairment do not require an adjustment in tamsulosin dosage. Tamsulosin has not been studied in patients with severe hepatic impairment.
