Duoflow Mechanism of Action

Pharmacology: Pharmacodynamics: DUOFLOW is a combination of two drugs with complementary mechanisms of action to improve symptoms in patients with BPH: dutasteride, a dual 5α-reductase inhibitor (5 ARI) and tamsulosin hydrochloride, an antagonist of α1a-adrenoreceptors.
The pharmacodynamics of DUOFLOW as a fixed dose 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). DHT is the androgen primarily responsible for hyperplasia of glandular prostatic tissue.
Dutasteride lowers DHT levels, reduces prostate volume, improved lower urinary tract symptoms and urine flow and reduces the risk of AUR and BPH-related surgery.
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 5 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 increases maximum urinary flow rate by reducing smooth muscle tension in the prostate and urethra, thereby relieving obstruction. It also improved the complex of irritative and obstructive symptoms in which bladder instability and tension of the smooth muscles of lower urinary tract play an important role. Alpha-1 adrenergic blockers can reduce blood pressure by lowering peripheral resistance.
Pharmacokinetics: Bioequivalence was demonstrated between DUOFLOW and original combination of dutasteride and tamsulosin.
Dutasteride: Absorption: Following administration of dutasteride 0.5 mg dose, peak serum concentrations of dutasteride occur within 2 to 3 hours.
Absolute bioavailability is approximately 60%.
Distribution: Volume of distribution is 300 to 500 L. Dutasteride is highly bound to plasma protein (Albumin (99%); alpha-1 acid glycoprotein (96.6%)). In a study of heathy subjects receiving dutasteride 0.5 mg/day for 12 months, semen dutasteride concentrations averaged 3.4 ng/mL (range, 0.4 to 14 ng/mL) at 12 months and, similar to serum, achieved steady-state concentrations at 6 months. On average, 11.5% of serum dutasteride concentrations partitioned into semen at 12 months.
Metabolism: Dutasteride is metabolized by the human cytochrome P450 isoenzymes CYP3A4/5.
In vitro, 2 dutasteride metabolites are much less potent than dutasteride against both isoforms of human 5-alpha reductase. The activity of another metabolite (6-beta-hydroxydutasteride) is comparable with that of dutasteride.
Elimination: Dutasteride is excreted primarily via feces (5% unchanged). Terminal half-life is 5 weeks.
Elderly: Dutasteride half-life increased with age (approximately 170 hours in men 20 to 49 years of age, approximately 260 hours in men 50 to 69 years of age, and approximately 300 hours in men older than 70 years).
Tamsulosin: Absorption: Essentially completely absorbed following oral administration under fasting conditions; peak plasma concentrations attained within 4-5 hours. Food delays time to peak plasma concentration by about 2 hours. When administered under fasting conditions, bioavailability and peak plasma concentration are increased by 30 and 40-70%, respectively, compared with fed state.
Distribution: Appears to distribute into extracellular fluids in humans. In animals, distributed into kidney, prostate, liver, gallbladder, heart, aorta, and brown fat, with minimal distribution into brain, spinal cord, and testes. Plasma protein binding is 94-99% (mainly to α1-acid glycoprotein).
In patients with moderate hepatic impairment, protein binding is altered, resulting in changes in overall plasma concentrations; however, no substantial alterations in intrinsic clearance and concentrations of unbound drug.
In patients with renal impairment, protein binding is altered, resulting in changes in overall plasma concentrations, however, no substantial alterations in intrinsic clearance and concentrations of unbound drug.
Metabolism: Extensively metabolized by CYP enzymes (specific isoenzyme(s) not identified) in the liver. Metabolites undergo further conjugation prior to excretion.
Elimination: Excreted in urine (76%) and feces (21%). Because of absorption rate-controlled pharmacokinetics of tamsulosin capsules, apparent half-life is about 9-13 hours in healthy individuals and 14-15 hours in patients with BPH.
Elderly: In males 55-75 years of age, intrinsic clearance is decreased and elimination half-life is prolonged, resulting in a 40% increase in AUC compared with males 20-32 years of age.