Source: Marketing Authorisation Holder Revision Year: 2013
Tamsulosin hydrochloride, an alpha1-adrenoceptor blocking agent, exhibits selectivity for alpha1-receptors in the human prostate. At least three discrete alpha1-adrenoceptor subtypes have been identified: alpha1A, alpha1B and alpha1D; their distribution differs between human organs and tissue. Approximately 70% of the alpha1-receptors in the human prostate are of the alpha1A subtype. Blockade of these adrenoreceptors can cause smooth muscles in the bladder neck and prostate to relax, resulting in an improvement in the urine flow rate and a reduction in the symptoms of BPH.
Dutasteride inhibits the conversion of testosterone to 5 alpha-dihydrotestosterone (DHT) by a competitive and specific inhibition of both the type I and type II isoforms of steroid 5 alpha-reductase (5AR). Testosterone is converted to DHT by the enzyme 5 alpha-reductase, which exists as 2 isoforms, type I and type II. The type II isoenzyme is primarily active in the reproductive tissues, while the type I isoenzyme is also responsible for testosterone conversion in the skin and liver. DHT is the androgen primarily responsible for the initial development and subsequent enlargement of the prostate gland.
The maximum effect of daily doses of dutasteride on the reduction of DHT is dose-dependent and is observed within 1-2 weeks. After 1 and 2 weeks of daily dosing with dutasteride 0.5 mg, median serum DHT concentrations were reduced by 85% and 90%, respectively. In patients with BPH treated with dutasteride 0.5 mg/day for 4 years, the median decrease in serum DHT was 94% at 1 year, 93% at 2 years, and 95% at both 3 and 4 years. The median increase in serum testosterone was 19% at both 1 and 2 years, 26% at 3 years, and 22% at 4 years, but the mean and median levels remained within the physiologic range.
In patients with BPH treated with 5 mg/day of dutasteride or placebo for up to 12 weeks prior to transurethral resection of the prostate, mean DHT concentrations in prostatic tissue were significantly lower in the dutasteride group compared with placebo (784 and 5,793 pg/g, respectively; p Adult males with genetically inherited type II 5 alpha-reductase deficiency also have decreased DHT levels. These 5 alpha-reductase deficient males have a small prostate gland throughout life and do not develop BPH. Except for the associated urogenital defects present at birth, no other clinical abnormalities related to 5 alpha-reductase deficiency have been observed in these individuals.
In healthy volunteers, 52 weeks of treatment with dutasteride 0.5 mg/day (n=26) resulted in no clinically significant change compared with placebo (n=23) in sex hormone-binding globulin, oestradiol, luteinizing hormone, follicle-stimulating hormone, thyroxine (free T4) and dehydroepiandrosterone. Statistically significant, baseline-adjusted mean increases compared with placebo were observed for total testosterone at 8 weeks (97.1 ng/dL, p<0.003) and thyroid-stimulating hormone at 52 weeks (0.4 mcIU/mL, p <0.05). The median percentage changes from baseline within the dutasteride group were 17.9% for testosterone at 8 weeks and 12.4% for thyroid stimulating hormone at 52 weeks. After stopping dutasteride for 24 weeks, the mean levels of testosterone and thyroid-stimulating hormone had returned to baseline in the group of subjects with available data at the visit. In patients with BPH treated with dutasteride in a large randomized, double-blind, placebo-controlled study, there was a median percent increase in the luteinizing hormone of 12% at 6 months and 19% at both 12 and 24 months.
Plasma lipid panel and bone mineral density were evaluated following 52 weeks of dutasteride 0.5 mg once daily in healthy volunteers. There was no change in bone mineral density as measured by dual energy x-ray absorptiometry (DEXA) compared with either placebo or baseline. In addition, the plasma lipid profile (i.e., total cholesterol, low-density lipoproteins, high-density lipoproteins and triglycerides) was unaffected by dutasteride. No clinically significant changes in adrenal hormone responses to ACTH stimulation were observed in a subset population (n=13) of the 1-year healthy volunteer study.
Absorption of tamsulosin hydrochloride 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 4-5 hours under fasting conditions and by 6-7 hours when tamsulosin hydrochloride capsules are administered with food.
The mean steady-state apparent volume of distribution of tamsulosin hydrochloride after intravenous administration to 10 healthy male adults was 16 L, which is suggestive of distribution into the extracellular fluids in the body. Tamsulosin hydrochloride is extensively bound to human plasma proteins (94-99%), primarily alpha1-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.
There is no enantiomeric bioconversion from tamsulosin hydrochloride to the S(+) isomer in humans. Tamsulosin hydrochloride is extensively metabolized by cytochrome (CY) P450 enzymes in the liver and less than 10% of the dose is excreted in the urine unchanged. However, the pharmacokinetic profile of the metabolites in humans has not been established. Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6 as well as via some minor participation of other CYP isoenzymes. Inhibition of hepatic drug-metabolizing enzymes may lead to increased exposure to tamsulosin hydrochloride. Inhibition of hepatic drug-metabolizing enzymes may lead to increased exposure to tamsulosin hydrochloride. The metabolites of tamsulosin hydrochloride undergo extensive conjugation to glucuronide or sulphate 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 (5 alpha-reductase inhibitor for treatment of BPH). However, results of the in vitro testing of the tamsulosin hydrochloride interaction with diclofenac and warfarin were equivocal.
On administration of the radiolabelled dose of tamsulosin hydrochloride to 4 healthy volunteers, 97% of the administered radioactivity was recovered, with urine (76%) representing the primary route of excretion compared to faeces (21%) over 168 hours. Because of absorption rate-controlled pharmacokinetics with tamsulosin hydrochloride modified-release capsules, the apparent half-life of tamsulosin hydrochloride is approximately 9-13 hours in healthy volunteers and 14-15 hours in the target population. Tamsulosin hydrochloride undergoes restrictive clearance in humans, with a relatively low systemic clearance (2.88 L/h).
Tamsulosin hydrochloride capsules are not indicated for use in paediatric populations.
Cross-study comparison of Tamsulosin hydrochloride capsules overall exposure (AUC) and half-life indicates 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.
The pharmacokinetics of tamsulosin hydrochloride have been compared in 6 subjects with mild-moderate (30 ≤ CLcr 2) or moderate-severe (10 ≤ CLcr 2) renal impairment and 6 normal subjects (CLcr >90 mL/min/1.73 m²). 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 end-stage renal disease (CLcr <10 mL/min/1.73 m²) have not been studied.
The pharmacokinetics of tamsulosin hydrochloride have been compared in 8 subjects with moderate hepatic impairment (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 impairment do not require an adjustment in tamsulosin hydrochloride capsules dosage. Tamsulosin hydrochloride has not been studied in patients with severe hepatic impairment.
Following administration of a single 0.5 mg dose of dutasteride, time to peak serum concentrations (T~max~) occurs within 2-3 hours. Absolute bioavailability in 5 healthy subjects is approximately 60% (range: 40% to 94%). When the drug is administered with food, the maximum serum concentrations were reduced by 10-15%. This reduction is of no clinical significance.
Pharmacokinetic data following single and repeat oral doses show that dutasteride has a large volume of distribution (300-500 L). Dutasteride is highly bound to plasma albumin (99.0%) and alpha1-acid glycoprotein (96.6%). In a study of healthy subjects (n = 26) 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, at 12 months 11.5% of serum dutasteride concentrations partitioned into semen.
Dutasteride is extensively metabolized in humans. In vitro studies showed that dutasteride is metabolized by the CYP3A4 and CYP3A5 isoenzymes. Both of these isoenzymes produced the 4'-hydroxydutasteride, 6-hydroxydutasteride and the 6,4'-dihydroxydutasteride metabolites. In addition, the 15-hydroxydutasteride metabolite was formed by CYP3A4. In human serum following dosing to a steady state, unchanged dutasteride, three major metabolites (4'-hydroxydutasteride, 1,2-dihydrodutasteride and 6-hydroxydutasteride) and two minor metabolites (6,4-dihydroxydutasteride and 15-hydroxydutasteride), as assessed by mass spectrometric response have been detected. In vitro, the 4-hydroxydutasteride and 1,2-dihydrodutasteride metabolites are much less potent than dutasteride against both isoforms of human 5 alpha-reductase. The activity of 6β-hydroxydutasteride is comparable to that of dutasteride.
Dutasteride and its metabolites were excreted mainly in the faeces. As a percent of dose, there was approximately 5% unchanged dutasteride (~1% to ~15%) and 40% as dutasteride-related metabolites (~2% to ~90%). Only trace amounts of unchanged dutasteride were found in urine (<1%). Therefore, on average, the dose unaccounted for approximated 55% (range: 5% to 97%).The terminal elimination half-life of dutasteride is approximately 5 weeks at the steady state. The average steady-state serum dutasteride concentration was 40 ng/mL following 0.5 mg/day for 1 year. Following daily dosing, dutasteride serum concentrations achieve 65% of steady-state concentration after 1 month and approximately 90% after 3 months. Due to the long half-life of dutasteride, serum concentrations remain detectable (greater than 0.1 ng/mL) for up to 4-6 months after discontinuation of treatment.
Dutasteride pharmacokinetics has not been investigated in subjects younger than 18 years of age.
No dose adjustment is necessary in the elderly. The pharmacokinetics and pharmacodynamics of dutasteride were evaluated in 36 healthy male subjects aged between 24 and 87 years following administration of a single 5 mg dose of dutasteride. In this single-dose trial, dutasteride half-life increased with age (approximately 170 hours in men aged 20 to 49 years, approximately 260 hours in men aged 50 to 69 years, and approximately 300 hours in men older than 70 years). Of 2,167 men treated with dutasteride in the three pivotal trials, 60% were aged 65 years and over, and 15% were aged 75 years and over. No overall differences in safety or efficacy were observed between these patients and younger patients.
Dutasteride is contraindicated in pregnancy and women of childbearing potential and is not indicated for use in other women. The pharmacokinetics of dutasteride in women has not been studied.
The effect of race on dutasteride pharmacokinetics has not been studied.
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 adjustment in dosage is anticipated for patients with renal impairment.
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.
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