Urief

Urief Mechanism of Action

silodosin

Manufacturer:

Synmosa

Distributor:

Synmosa
Full Prescribing Info
Action
Pharmacology: Pharmacodynamics: Pharmacological Effects: Effects in human tissue: Affinity to α-adrenergic receptors in the sympathetic nervous system: In a receptor-binding assay on human α1-adrenergic receptors, silodosin showed a high affinity to the α1A-adrenergic receptor subtype.
Effect on prostate gland: In a receptor-binding assay using human prostate membrane specimens, silodosin showed a high affinity to the α1A-adrenergic receptor subtype.
Silodosin inhibited noradrenalin-induced contractions of human prostate smooth muscle.
Effects in animals: Effect on lower urinary tract tissue (prostate, urethra, and trigone of bladder): Silodosin exhibited a potent antagonistic action against noradrenalin-induced contractions in isolated rabbit prostate, urethra, and trigone of bladder.
Effect on urethral pressure: In anesthetized male rats, phenylephrine-induced increases in urethral pressure in the region of the prostate were selectively inhibited by silodosin. The inhibitory dose was lower than hypotensive dose.
In anesthetized male dogs, increased urethral pressure in the region of the prostate due to electrical stimulation of the hypogastric nerve was also selectively inhibited by silodosin. The inhibitory dose was lower than hypotensive dose.
Effect in prostatic hypertrophy model: In a male rat prostatic hypertrophy model prepared by administration of sex hormone, bladder irritation symptoms associated with urinary retention were inhibited.
Mechanism of Action: By blocking the sympathetic nervous system, which mediates the α1A-adrenoceptor subtype which is distributed in lower urinary tract tissue (prostate, urethra, and trigone of bladder), silodosin reduces smooth muscle tone of lower urinary tract tissue and inhibits increases in urethral pressure, thereby improving lower urinary tract symptoms associated with benign prostatic hyperplasia.
Clinical Studies:
Phase II Double-Blind Comparative Studynote): When URIEF Cap. at a dose of 2 or 4 mg, or placebo was administered orally twice daily for 4 weeks to patients with lower urinary tract symptoms associated with benign prostatic hyperplasia, subjective symptoms (total I-PSS) were significantly improved in the 4-mg group compared to the placebo group (Table 2).
note): Silodosin (capsule) data.
See Table 2.

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Phase III Double-blind Comparative Studynote): When URIEF Cap. (silodosin) at a dose of 4 mg or placebo was administered orally twice daily for 12 weeks to patients with lower urinary tract symptoms associated with benign prostatic hyperplasia, the total I-PSS in the silodosin and placebo groups on completion of the study showed a decrease of 8.3 and 5.3 points, respectively, compared to baseline (Fig. 1, Table 3). The percentage (%) of patients in the silodosin and placebo groups whose total I-PSS improved by at least 25% compared to baseline was 76.4% (133/174 patients) and 50.6% (45/89 patients), respectively. The percentage (%) of patients in the silodosin and placebo groups whose symptoms improved to mild (total I-PSS: < 8) was 47.7% (83/174 patients) and 31.5% (28/89 patients), respectively. In the silodosin group, an improvement in subjective symptoms was seen from as early as Wk 1 and an improvement effect was also observed in patients whose symptoms were severe.
note): Silodosin (capsule) data.
See Figure 1 and Table 3.

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Long-term Administration Studynote): In a long-term administration study, URIEF Cap. was administered at a dose of 4 mg twice daily for 52 weeks to 364 patients with lower urinary tract symptoms associated with benign prostatic hypertrophy. A continuous improvement effect and drug safety were reported and stable subjective symptoms (total I-PSS) and improvement in maximum urine flow rate were observed.
note): Silodosin (capsule) data.
Pharmacokinetics: Absorption and Plasma Concentrations: When a single oral dose of URIEF Cap. was administered to healthy adult male volunteers (6 subjects/group) at doses ranging from 0.5 to 12 mg, plasma concentrations of silodosin increased dose-dependently, and Cmax and AUC0-∞ showed linearity. The time course of changes in plasma concentrations of silodosin following a single oral administration of URIEF Cap. at a dose of 2 or 4 mg is shown in Figure 2. (See Figure 2.)

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When URIEF Cap. were administered orally twice daily for 7 days (once daily on days 1 and 7) at a dose of 4 mg/dose in 5 healthy adult male volunteers, plasma concentrations of silodosin reached a steady state on day 3. The accumulation factor relative to the first dose was 1.1-fold. (Table 4).

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Pharmacokinetic parameters following repeated administration are shown as the results obtained from the time course of changes in concentration on day 7 less the cumulative concentration from days 0 - 6.
When a single 4 mg dose of URIEF Cap. was administered orally to 12 elderly males (age range: 65 to 75 years old) postprandially, no obvious differences in the pharmacokinetic profile were observed compared to that in 9 non-elderly (age range: 21 to 31 years old) males. The pharmacokinetic parameters in elderly males who received treatment with URIEF Cap. are shown in Table 5. (See Table 5.)

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When a single 4 mg dose of URIEF Cap. was administered orally to 11 healthy adult male volunteers 30 min postprandially or under fasting conditions, the Cmax, AUC0-48hr, Tmax, and t½ following postprandial administration (or under fasting conditions) were 23.0 (28.0) ng/mL, 128.8 (135.9) ng·hr/mL, 2.1 (1.4) hr, and 6.0 (4.7) hr, respectively (Table 6). (See Table 6.)

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The clearance and distribution volume following administration of silodosin solution (2 mg) to 11 healthy adult male volunteers by intravenous infusion over 4 hr were 167.0±33.8 mL/min and 49.5±17.3 L, respectively. The bioavailability following a single oral administration of URIEF Cap. at a dose of 4 mg was 32.2%.
Protein Binding: In an in vitro study, the human plasma-protein binding rate of silodosin was 95.6% (at a concentration of 100 ng/mL) and the main binding protein was α1-acid glycoprotein.
Metabolism and Excretion: Silodosin was metabolised mainly by CYP3A4, UGTs, ADH, and ALDH, with the major metabolites in plasma being a glucuronide and an oxidized metabolite of silodosin. When a single 8 mg dose of 14C-labeled silodosin was administered orally to 6 healthy male non-Japanese volunteers, the AUC0-12hr of silodosin and its glucuronide and oxidized metabolites relative to the AUC0-12hr of total radioactivity in plasma was 24.0, 21.9, and 34.9%, respectively. Other metabolites accounted for no more than 5%. In the 240-hour period after dosing, 33.5 and 54.9% of administered radioactivity was excreted in urine and feces, respectively.
The cumulative excretion in urine 0-48 hr after a single 4 mg dose of URIEF Cap. was administered orally to 12 elderly and 9 non-elderly male volunteers was 2.3 and 2.4% for silodosin, 1.6 and 1.8% for its glucuronide metabolite, and 4.5 and 4.9% for its oxidised metabolite, respectively.
Pharmacokinetics in Patients with Lower Urinary Tract Symptoms Associated with Benign Prostatic Hyperplasianote): In an exploratory population pharmacokinetic analyses (n=258) of a long-term administration study with URIEF Cap. in patients with lower urinary tract symptoms associated with benign prostatic hyperplasia, the estimated plasma concentrations of silodosin (mean±SD) at steady state 2 and 12 hours post-dose were 24.8±8.0 and 7.4±3.3 ng/mL, respectively.
An analysis of variable factors in relation to plasma concentrations of silodosin suggested that silodosin clearance is affected by body weight, age, CRP, ALT (GPT), and serum creatinine and distribution volume by body weight, age, CRP, and ALT (GPT). Of these factors, it was concluded that ALT (GPT) had the most effect on plasma concentrations of silodosin and it was suggested that, as a result of increased levels of ALT (GPT) (23→83 IU/L), silodosin clearance and distribution volume may decrease by approximately 47 and 27%, respectively.
note): Silodosin (capsule) data.
Drug Interaction(s): Non-Japanese data: Ketoconazole (oral preparation not marketed in Japan) coadministration: When 16 healthy male volunteers (non-Japanese) who were receiving 200 mg of ketoconazole (p.o.) once daily for 4 days were coadministered a single 4 mg dose of URIEF Cap. (p.o.) on day 2, Cmax and AUC0-∞ of silodosin increased 3.7- and 2.9-fold, respectively, compared to when silodosin alone was administered.
Digoxin coadministration: When URIEF Cap. (4 mg, twice daily) was coadministered orally with digoxin (0.25 mg, once daily) for 8 days to 16 healthy male volunteers (non-Japanese), it was confirmed that URIEF Cap. has no effect on the pharmacokinetic profile of digoxin.
Pharmacokinetics in Patients with Impaired Renal Function: When a single 4 mg dose of URIEF Cap. was administered orally to 6 patients with impaired renal function (creatinine clearance: 27-49 mL/min) and 7 volunteers with normal renal function (creatinine clearance: 125-176 mL/min), the total plasma concentration of silodosin was increased (Cmax: 3.1-fold; AUC0-∞: 3.2-fold) in patients with impaired renal function compared to that in the volunteer group. This increase in total plasma concentration of silodosin may be attributable to protein binding with serum α1-acid glycoprotein, with a high correlation between total plasma concentration of silodosin and serum concentration of α1-acid glycoprotein observed. It should be noted that the increase in the plasma concentration of unbound silodosin (Cmax: 1.5-fold; AUC0-∞: 2.0-fold), which is considered to have a direct bearing on the manifestation of drug effect and incidence of adverse reactions associated with silodosin, was less than that for the total drug concentration (Table 7). (See Table 7.)

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