Silodosin - How It Works

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Silodosin is a selective antagonist of post-synaptic alpha-1 adrenoreceptors, which are located in the human prostate, bladder base, bladder neck, prostatic capsule, and prostatic urethra.

Blockade of these alpha-1 adrenoreceptors can cause smooth muscle in these tissues to relax, resulting in an improvement in urine flow and a reduction in BPH symptoms.

An in vitro study examining binding affinity of silodosin to the three subtypes of the alpha-1 adrenoreceptors (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.

12.2 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 Warnings and Precautions ].

Table 2: Summary of Orthostatic Test Results in 12-week, Placebo-Controlled Clinical Trials Time of Measurement Test Result Silodosin Capsules N=466 n (%) Placebo N=457 n (%) 1 Minute After Standing Negative Positive 459 6 454 2 3 Minutes After Standing Negative Positive 456 9 454 2 Cardiac Electrophysiology The effect of silodosin capsules 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 capsules 8 mg, silodosin capsules 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 capsules was selected to achieve blood levels of silodosin that may be seen in a “worst-case” scenario exposure (i.e., in the setting of concomitant renal disease or use of strong CYP3A4 inhibitors) [ see Contraindications , Warnings and Precautions and Clinical Pharmacology ].

QT interval was measured during a 24-hour period following dosing on Day 5 (at silodosin steady state).

Silodosin capsules 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.

There has been no signal of Torsade de Pointes in the post-marketing experience with silodosin outside the United States.

12.3 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 3 presents the steady state pharmacokinetics of this study.

Table 3: Mean (±SD) Steady State Pharmacokinetic Parameters in Healthy Males Following Silodosin 8 mg Once Daily with Food C max (ng/mL) t max (hours) t 1/2 (hours) AUC ss (ng•hr/mL) 61.6 ± 27.54 2.6 ± 0.9 13.3 ± 8.07 373.4 ± 164.94 C max = maximum concentration, t max = time to reach C max , t 1/2 = elimination half-life, AUC ss = steady state area under the concentration-time curve Figure 1: Mean (±SD) Silodosin Steady State Plasma Concentration-Time Profile in Healthy Target-Aged Subjects Following Silodosin 8 mg Once Daily with Food The absolute bioavailability is approximately 32%.

Food 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.