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An in vitro study examining binding affinity of silodosin to the three subtypes of the alpha-1 adrenoceptors (alpha-1A, alpha-1B, and alpha-1D) was conducted. The results of the study demonstrated that Silodosin binds with high affinity to the alpha-1A subtype.
Pharmacodynamics: Orthostatic Effects: A test for postural hypotension was conducted 2 to 6 hours after the first dose in the two 12-week, double-blind, placebo-controlled clinical studies. After the patient had been at rest in a supine position for 5 minutes, the patient was asked to stand. Blood pressure and heart rate were assessed at 1 minute and 3 minutes after standing. A positive result was defined as a >30 mmHg decrease in systolic blood pressure, or a > 20 mmHg decrease in diastolic blood pressure, or a >20 bpm increase in heart rate. (See Table 1.)
Click on icon to see table/diagram/imageCardiac Electrophysiology: The effect of Silodosin on QT interval was evaluated in a double-blind, randomized, active-(moxifloxacin) and placebo-controlled, parallel-group study in 189 healthy male subjects aged 18 to 45 years. Subjects received either Silodosin 8 mg, Silodosin 24 mg, or placebo once daily for five days, or a single dose of moxifloxacin 400 mg on Day 5 only. The 24 mg dose of Silodosin was selected to achieve blood levels of Silodosin that may be seen in "worst-case" scenario exposure (i.e., in the setting of concomitant renal disease or use of strong CYP3A4 inhibitors). QT interval was measured during a 24-hour period following dosing on Day 5 (at Silodosin steady state).
Silodosin was not associated with an increase in individual corrected (QTcI) QT interval at any time during steady state measurement, while moxifloxacin, the active control, was associated with a maximum 9.59 msec increase in QTcI.
Pharmacokinetics: The pharmacokinetics of Silodosin have been evaluated in adult male subjects with doses ranging from 0.1 mg to 24 mg per day. The pharmacokinetics of Silodosin are linear throughout this dosage range.
Absorption: The pharmacokinetic characteristics of Silodosin 8 mg once daily were determined in a multi-dose, open-label, 7-day pharmacokinetic study completed in 19 healthy, target-aged (≥45 years of age) male subjects. Table 2 presents the steady state pharmacokinetics of this study. (See Table 2 and Figure.)
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Click on icon to see table/diagram/imageFood Effect: The maximum effect of food (i.e., co-administration with a high fat, high calorie meal) on the PK of Silodosin was not evaluated. The effect of a moderate fat, moderate calorie meal was variable and decreased Silodosin Cmax by approximately 18 to 43% and AUC by 4 to 49% across three different studies.
In a single-center, open-label, single-dose, randomized, two-period crossover study in twenty healthy male subjects age 21 to 43 years under fed conditions, a study was conducted to evaluate the relative bioavailability of the contents of an 8 mg capsule (size #1) of Silodosin sprinkled on applesauce compared to the product administered as an intact capsule. Based on AUC0-24 and Cmax, Silodosin administered by sprinkling the contents of a Silodosin capsule onto a tablespoonful of applesauce was found to be bioequivalent to administering the capsule whole.
Distribution: Silodosin has an apparent volume of distribution of 49.5 L and is approximately 97% protein bound.
Metabolism: Silodosin undergoes extensive metabolism through glucuronidation, alcohol and aldehyde dehydrogenase, and cytochrome P450 3A4 (CYP3A4) pathways. The main metabolite of Silodosin is a glucuronide conjugate (KMD-3213G) that is formed via direct conjugation of Silodosin by UDP-glucuronosyltransferase 2B7 (UGT2B7). Co-administration with inhibitors of UGT2B7 (e.g., probenecid, valproic acid, and fluconazole) may potentially increase exposure to Silodosin. KMD-3213G, which has been shown in vitro to be active, has an extended half-life (approximately 24 hours) and reaches plasma exposure (AUC) approximately four times greater than that of Silodosin. The second major metabolite (KMD-3293) is formed via alcohol and aldehyde dehydrogenases and reaches plasma exposures similar to that of Silodosin. KMD-3293 is not expected to contribute significantly to the overall pharmacologic activity of Silodosin.
Excretion: Following oral administration of 14C-labeled Silodosin, the recovery of radioactivity after 10 days was approximately 33.5% in urine and 54.9% in feces. After intravenous administration, the plasma clearance of Silodosin was approximately 10 L/hour.
Special Populations: Race: No clinical studies specifically investigating the effects of race have been performed.
Geriatric: In a study comparing 12 geriatric males (mean age of 69 years) and 9 young males (mean age of 24 years), the exposure (AUC) and elimination half-life of Silodosin were approximately 15% and 20%, respectively, greater in geriatric than young subjects. No difference in the Cmax of Silodosin was observed.
Pediatric: Silodosin has not been evaluated in patients less than 18 years of age.
Renal Impairment: In a study with six subjects with moderate renal impairment, the total Silodosin (bound and unbound) AUC, Cmax, and elimination half-life were 3.2-, 3.1-, and 2-fold higher, respectively, compared to seven subjects with normal renal function. The unbound Silodosin AUC and Cmax were 2.0- and 1.5-fold higher, respectively, in subjects with moderate renal impairment compared to the normal controls.
In controlled and uncontrolled clinical studies, the incidence of orthostatic hypotension and dizziness was greater in subjects with moderate renal impairment treated with 8 mg Silodosin daily than in subjects with normal or mildly impaired renal function.
Hepatic Impairment: In a study comparing nine male patients with moderate hepatic impairment (Child-Pugh scores 7 to 9), to nine healthy male subjects, the single dose pharmacokinetic disposition of Silodosin was not significantly altered in patients with moderate hepatic impairment. No dosing adjustment is required in patients with mild or moderate hepatic impairment. The pharmacokinetics of Silodosin in patients with severe hepatic impairment have not been studied.
Drug Interactions: Cytochrome P450 (CYP) 3A4 Inhibitors: Two clinical drug interaction studies were conducted in which a single oral dose of Silodosin was co-administered with strong CYP3A4 inhibitor, ketoconazole, at doses of 400 mg and 200 mg, respectively, once daily for 4 days. Co-administration of 8 mg Silodosin with 400 mg ketoconazole led to 3.8-fold increase in Silodosin Cmax and 3.2-fold increase in AUC. Co-administration of 4 mg Silodosin with 200 mg ketoconazole led to similar increases: 3.7- and 2.9-fold in Silodosin Cmax and AUC, respectively. Silodosin is contraindicated with strong CYP3A4 inhibitors.
The effect of moderate CYP3A4 inhibitors on the pharmacokinetics of Silodosin has not been evaluated. Due to the potential for increased exposure to Silodosin, caution should be exercised when co-administering Silodosin with moderate CYP3A4 inhibitors, particularly those that also inhibit P-glycoprotein (e.g., verapamil, erythromycin).
P-glycoprotein (P-gp) inhibitors: In-vitro studies indicated that Silodosin is a P-gp substrate. A drug interaction study with strong P-gp inhibitor has not been conducted. However, in drug interaction studies with ketoconazole, a CYP3A4 inhibitor that also inhibits P-gp, significant increase in exposure to Silodosin was observed. Inhibition of P-gp may lead to increased Silodosin concentration. Silodosin is not recommended in patients taking strong P-gp inhibitors (e.g., cyclosporine).
Digoxin: The effect of Silodosin on the pharmacokinetics of digoxin was evaluated in a multiple dose, single-sequence, crossover study of 16 healthy males, aged 18 to 45 years. A loading dose of digoxin was administered as 0.5 mg twice daily for one day. Following the loading doses, digoxin (0.25 mg once daily) was administered alone for seven days and then concomitantly with Silodosin 4 mg twice a day for the next seven days. No significant differences in digoxin AUC and Cmax were observed when digoxin was administered alone or concomitantly with Silodosin.
Other Metabolic Enzymes and Transporters: In vitro studies indicated that Silodosin administration is not likely to inhibit the activity of CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 or induce the activity of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4, and P-gp.
Toxicology: Preclinical safety data: In a 2-year oral carcinogenicity study in rats administered doses up to 150 mg/kg/day [about 8 times the exposure of the maximum recommended human dose (MRHE) based on AUC of Silodosin], an increase in thyroid follicular cell tumor incidence was seen in male rats receiving doses of 150 mg/kg/day. Silodosin induced stimulation of thyroid stimulating hormone (TSH) secretion in the male rat as a result of increased metabolism and decreased circulating levels of thyroxine (T4). These changes are believed to produce specific morphological and functional changes in the rat thyroid including hypertrophy, hyperplasia, and neoplasia. Silodosin did not alter TSH or T4 levels in clinical trials and no effects based on thyroid examinations were noted. The relevance to human risk of these thyroid tumors in rats is not known.
In a 2-year oral carcinogenicity study in mice administered doses up to 100 mg/kg/day in males (about nine times the MRHE based on AUC of Silodosin) and 400 mg/kg/day in females (about 72 times the MRHE based on AUC), there were no significant tumor findings in male mice. Female mice treated for 2 years with doses of 150 mg/kg/day (about 29 times the MRHE based on AUC) or greater had statistically significant increases in the incidence of mammary gland adenoacanthomas and adenocarcinomas. The increased incidence of mammary gland neoplasms in female mice was considered secondary to Silodosin-induced hyperprolactinemia measured in the treated mice. Elevated prolactin levels were not observed in clinical trials. The relevance to human risk of prolactin-mediated endocrine tumors in mice is not known. Rats and mice do not produce glucuronidated Silodosin, which is present in human serum at approximately four times the level of circulating Silodosin and which has similar pharmacological activity to Silodosin.
