Tamplus Mechanism of Action

Pharmacology: Pharmacodynamics: Finasteride: The symptoms associated with Benign Prostatic Hyperplasia (BPH) are related to bladder outlet obstruction, which is comprised of two underlying components: static and dynamic. The static component is related to an increase in prostate size caused, in part, by a proliferation of smooth muscle cells in the prostatic stroma. The development and enlargement of the prostate gland is dependent on 5α-dihydrotestosterone (DHT), a potent androgen. Type II 5α-reductase metabolizes testosterone to DHT in the prostate. Finasteride is a competitive and specific inhibitor of Type II 5α-reductase with which it slowly forms a stable enzyme complex. Finasteride reduces serum DHT concentrations and produces a sustained regression in prostate volume of approximately 20% and a sustained increase in urinary flow rate.
Tamsulosin: The symptoms associated with Benign Prostatic Hyperplasia (BPH) are related to bladder outlet obstruction, which is comprised of two underlying components: static and dynamic. The dynamic component is a function of an increase in smooth muscle tone in the prostate and bladder neck leading to constriction of the bladder outlet. Smooth muscle tone is mediated by the sympathetic nervous stimulation of α₁ adrenoceptors, which are abundant in the prostate, prostatic capsule, prostatic urethra, and bladder neck. Blockade of these adrenoceptors can cause smooth muscles in the bladder neck and prostate to relax, resulting in an improvement in urine flow rate and a reduction in symptoms of BPH. Tamsulosin, a α₁ adrenoceptor blocking agent, exhibits selectivity for α₁ receptors in the human prostate. At least three discrete α₁-adrenoceptor subtypes have been identified: α₁A, α₁B and α₁D; their distribution differs between human organs and tissue. Approximately 70% of the α₁-receptors in human prostate are of the α₁A subtype. Tamsulosin hydrochloride capsules are not intended for use as an antihypertensive drug.
Pharmacokinetics: Finasteride: Absorption: In healthy young subjects, the mean bioavailability of Finasteride 5-mg tablets was 63% (range 34-108%). Maximum Finasteride plasma concentration averaged 37 ng/mL (range, 27-49 ng/mL) and was reached 1-2 hours post dose. Bioavailability of Finasteride was not affected by food.
Distribution: Mean steady-state volume of distribution was 76 liters (range, 44-96 liters). Approximately 90% of circulating Finasteride is bound to plasma proteins.
Metabolism: Finasteride is extensively metabolized in the liver, primarily via the cytochrome P450 3A4 enzyme subfamily. Two metabolites, the t-butyl side chain monohydroxylated and monocarboxylic acid metabolites possess no more than 20% of the 5α-reductase inhibitory activity of Finasteride.
Elimination: In healthy young subjects, the mean plasma clearance of Finasteride was 165 mL/min (range, 70-279 mL/min) and the mean elimination half-life in plasma was 6 hours (range, 3-16 hours). Following an oral dose of 14C-finasteride in man, a mean of 39% (range, 32-46%) of the dose was excreted in the urine in the form of metabolites; 57% (range, 51-64%) was excreted in the feces. The mean terminal half-life of Finasteride in subjects ≥70 years of age was approximately 8 hours (range, 6-15 hours), compared with 6 hours (range, 4-12 hours; n=12) in subjects 45-60 years of age. As a result, mean AUC (0-24 hr) after 17 days of dosing was 15% higher in subjects ≥70 years of age than in subjects 45-60 years of age.
Elderly: The elimination rate of Finasteride is decreased in the elderly (See Elimination as previously-mentioned); these findings however are of no clinical significance.
Patients with Renal Impairment: In patients with chronic renal impairment (CrCl 9.0-55 mL/min), AUC, maximum plasma concentration, half-life, and protein binding after a single dose of 14C-finasteride was similar to values obtained in healthy volunteers. Urinary excretion of metabolites was decreased in patients with renal impairment. This decrease was associated with an increase in fecal excretion of metabolites. Plasma concentrations of metabolites were significantly higher in patients with renal impairment (based on a 60% increase in total radioactivity AUC). However, Finasteride has been well tolerated in BPH patients with normal renal function receiving up to 80 mg/day for 12 weeks, where exposure of these patients to metabolites would presumably be much greater.
Patients with Hepatic Impairment: The effect of hepatic insufficiency on Finasteride pharmacokinetics has not been studied. Caution should be exercised when Finasteride is administered in patients with liver function abnormalities, as Finasteride is metabolized extensively in the liver.
Tamsulosin: Absorption: Absorption of Tamsulosin hydrochloride from 400 mcg capsules is essentially complete (>90%) following oral administration under fasting conditions. Tamsulosin hydrochloride exhibits linear kinetics following single and multiple dosing, with achievement of steady-state concentrations by the fifth day of once-a-day dosing. The time to maximum concentration (Tmax) is reached by four to five hours under fasting conditions and by six to seven hours when the dose is administered with food. Taking Tamsulosin capsules under fasted conditions results in a 30% increase in bioavailability (AUC) and 40% to 70% increase in peak concentrations (Cmax) compared to fed conditions. The effects of food on the pharmacokinetics of Tamsulosin hydrochloride are consistent regardless of whether it is taken with a light breakfast or a high-fat breakfast.
Distribution: The mean steady-state apparent volume of distribution of Tamsulosin hydrochloride after intravenous administration to ten healthy male adults was 16L, which is suggestive of distribution into extracellular fluids in the body. Tamsulosin hydrochloride 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 ng/mL). The results of two-way in vitro studies indicate that the binding of Tamsulosin hydrochloride to human plasma proteins is not affected by amitriptyline, diclofenac, glyburide, simvastatin plus simvastatin-hydroxy acid metabolite, warfarin, diazepam, propranolol, trichlormethiazide, or chlormadinone. Likewise, Tamsulosin hydrochloride had no effect on the extent of binding of these drugs.
Metabolism: 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 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. Incubations with human liver microsomes showed no evidence of clinically significant metabolic interactions between Tamsulosin hydrochloride and amitriptyline, albuterol (beta agonist), glyburide (glibenclamide) and Finasteride (5alpha-reductase inhibitor for treatment of BPH). However, results of the in vitro testing of the Tamsulosin hydrochloride interaction with diclofenac and warfarin were equivocal.
Elimination: On administration of a radio labeled dose of Tamsulosin hydrochloride to four healthy volunteers, 97% of the administered radioactivity was recovered, with urine (76%) representing the primary route of excretion compared to feces (21%) over 168 hours. Following intravenous or oral administration of an immediate-release formulation of Tamsulosin, the elimination half-life of Tamsulosin hydrochloride in plasma ranged from five to seven hours. The apparent half-life of tamsulosin hydrochloride in this modified release formulation is approximately 9 to 13 hours in healthy volunteers and 14 to 15 hours in the target population. Tamsulosin hydrochloride undergoes restrictive clearance in humans, with a relatively low systemic clearance (2.88 L/h).
Elderly: Cross-study comparison of AUC and half-life indicate that the pharmacokinetic disposition of Tamsulosin hydrochloride may be slightly prolonged in geriatric 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.
Patients with Renal Impairment: The pharmacokinetics of Tamsulosin hydrochloride have been compared in 6 subjects with mild-moderate (30 ≤ CrCl < 70 mL/min/1.73m²) or moderate-severe (10 ≤ CrCl < 30 mL/min/1.73m²) renal impairment and 6 normal subjects (CrCl < 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 dosage. However, patients with end stage renal disease (CrCl <10 mL/min/1.73 m²) have not been studied.
Patients with Hepatic Impairment: The pharmacokinetics of Tamsulosin hydrochloride has 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 dosage. Tamsulosin hydrochloride has not been studied in patients with severe hepatic dysfunction.