Safety and efficacy of silodosin for the treatment of benign prostatic hyperplasia

Figures & data

Table 1 Affinity and selectivity for human α₁-AR subtype for silodosin and other α₁-AR antagonists

Compound	Ki value (nmol/L)			α1-AR subtype selectivity^a
	α1A-AR	α1B-AR	α1D-AR	α1A/α1B ratio	α1D/α1B ratio
Silodosin	0.039 ± 0.006	6.5 ± 0.6	2.2 ± 0.1	162	2.95
Tamsulosin hydrochloride	0.012 ± 0.002	0.12 ± 0.00	0.030 ± 0.005	9.55	3.80
Naftopidil	23 ± 7	7.8 ± 0.0	4.4 ± 0.4	0.372	1.78
Prazosin hydrochloride	0.12 ± 0.01	0.028 ± 0.002	0.078 ± 0.007	0.204	0.316
WB4101 hydrochloride	0.17 ± 0.01	1.1 ± 0.1	0.22 ± 0.04	6.03	5.01
BMY7378 dihydrochloride	75 ± 21	28 ± 7	0.43 ± 0.06	0.389	64.6

Notes: The K_i value in the table presents the mean ± standard error of 3 experiments. The subtype selectivity (α_1A/α_1B and α_1D/α_1B ratios) was calculated from the ratio after converting the concentration, specifically, using 10M [M = pK_i (α_1A or α_1D) – pK_i (α_1B)].

Reproduced with permission from Yakugaku Zasshi Vol 126 Special issue. Copyright © 2006 Pharmaceutical Society of Japan.²³

Table 2 pA₂ or pK_b values of silodosin and other α₁-AR antagonists for noradrenaline-induced contraction in the isolated rabbit prostate, urethra and bladder, and in the isolated rat spleen and thoracic aorta

Compound	pA2 or pKbvalues
	α1A-AR			α1B-AR	α1D-AR
	Prostate^a	Urethra^a	Bladder trigone^a	Spleen^b	Thoracic aorta^b
Silodosin	9.60 ± 0.05^c	8.71 ± 0.09 (0.98 ± 0.32)	9.35 ± 0.15^c	7.15 ± 0.05 (0.67 ± 0.09*)	7.88 ± 0.05 (1.00 ± 0.18)
Tamsulosin hydrochloride	9.93 ± 0.07^c	9.00 ± 0.06 (1.16 ± 0.27)	9.48 ± 0.14^c	8.64 ± 0.06 (0.61 ± 0.18*)	9.82 ± 0.06 (0.91 ± 0.20)
Naftopidil	6.69 ± 0.05^c (1.13 ± 0.21)	6.48 ± 0.11 (0.93 ± 0.39)	6.80 ± 0.07 (0.91 ± 0.25)	6.30 ± 0.07 (0.69 ± 0.23)	7.48 ± 0.06 (1.14 ± 0.23)
Prazosin hydrochloride	7.91 ± 0.02 (1.08 ± 0.09)	7.96 ± 0.04 (0.85 ± 0.13*)	8.10 ± 0.05 (0.97 ± 0.18)	9.34 ± 0.13 (0.56 ± 0.26*)	9.17 ± 0.06 (1.11 ± 0.23)

Notes: Each value in the table presents mean ± standard error of 4–5 animals. Each value in a parenthesis presents the slop of the Schild plot. a) Rabbits, b) Rats, c) pK;

b value.

* Significantly different from the unity at P < 0.05 by paired-t test.

Abbreviations: pA₂, negative logarithmic value of molar concentration of antagonistic blockers necessary to parallel shift 2 times the independent stimulant concentration-reaction curve to the higher concentration side; pK_b value, negative logarithmic value of dissociation constant for binding of antagonistic blockers to receptors.

Reproduced with permission from Yakugaku Zasshi Vol 126 Special issue. Copyright © 2006 Pharmaceutical Society of Japan.²³

Table 3 ID₅₀ value, ED₁₅ value and uroselectivity of silodosin and other α₁-AR antagonists after intravenous administration in the anesthetized rat

Drug	IUP	MBP	Uroselectivity
	ID50 (μg/kg)	ED15 (μg/kg)	(ED15/ID50)
Silodosin	0.932	10.9	11.7
Tamsulosin hydrochloride	0.400	0.895	2.24
Naftopidil	361	48.1	0.133
Prazosin hydrochloride	4.04	0.792	0.196

Notes: ID₅₀ value (the dose to suppress IUP increase by 50%); ED₁₅ value (the dose to decrease the MBP by 15%).

Reproduced with permission from Yakugaku Zasshi Vol 126 Special issue. Copyright © 2006 Pharmaceutical Society of Japan.²⁵

Table 4 Results of pivotal Phase III clinical trials

Study	Patients (n)		Baseline	Change	Baseline	Change
			IPSS, mean (SD)		Qmax, mean (SD), mL/sec
Kawabe et al^Citation27
Silodosin 8 mg/day	175		17.1 (5.7)	−8.3 (6.4)*	9.88 (2.75)		1.70 (3.31)
Tamsulosin 0.2 mg/day	192		17.0 (5.7)	−6.8 (5.7)	9.41 (2.81)		2.60 (3.98)
Placebo	89		17.1 (6.1)	−5.3 (6.7)	0.18 (2.72)		0.26 (2.21)
Marks et al^Citation28 (Pooled US studies)
Silodosin 8 mg/day		466	21.3 (5.1)	−6.4 (6.63)*	8.7 (2.60)		2.6 (4.43)*
Placebo		457	21.3 (4.9)	−3.5 (5.84)	8.9 (2.80)		1.5 (4.36)
Chapple et al^Citation29		(ITT population)
Silodosin 8 mg/day		371	19(4)	−7.0: −2.3 [–3.2, −1.4]*	10.78 (n = 381)		3.77
Tamsulosin 0.4 mg/day		376	19 (4)	−6.7: −2.0 [–2.9. −1.1]*	10.27 (n = 384)		3.53
Placebo		185	19 (4)	−4.7	10.32 (n = 190)		2.93
			IPSS voiding symptoms, mean (SD)		IPSS storage symptoms, mean (SD)
Kawabe et al^Citation27
Silodosin 8 mg/day		175	10.8 (4.1)	−5.8 (4.6)*	6.4 (3.0)	–2.5 (2.9)*
Tamsulosin 0.2 mg/day		192	10.8 (4.2)	−4.8 (4.1)	6.2 (2.9)	–2.1 (2.6)
Placebo		89	10.9 (4.4)	−3.8 (4.8)	6.3 (2.8)	–1.5 (2.6)
Marks et al^Citation28 (Pooled US studies)
Silodosin 8 mg/day	466		12 (3.6)	−4.0 (4.31)*	9.3 (2.6)	–2.3 (2.93)*
Placebo	457		12 (3.5)	−2.1 (3.76)	9.3 (2.5)	–1.4 (2.99)
Chapple et al^Citation29
Silodosin 8 mg/day	381		11.3 (3.13)	−4.5: −1.7: [–2.2, −1.1]*	7.9 (2.49)	–2.5: −0.7 [–1.1, −0.2]*
Tamsulosin 0.4 mg/day	384		11.0 (3.27)	−4.2: −1.4 [–2.0, −0.8]*	7.9 (2.51)	−2.4: −0.6 [−1.1, −0.2]*
Placebo	190		11.3 (3.22)	−4.7	8.0 (2.64)	−1.8

Note:

* Significant difference versus placebo.

Abbreviations: IPSS, International Prostate Symptom Score; Q_max, maximum flow rate; SD, standard deviation; ITT, intention to treat; [95% CI: confidence interval]

Figure 1 Time course of change in International Prostate Symptom Score in randomized, placebo-controlled, double-blind Phase III study.

Copyright © 2006, John Wiley and Sons. Reproduced with permissions from Kawabe et al.²⁷

Table 5 Adverse effects of silodosin compared with tamsulosin and placebo

Adverse effects	Silodosin (%)	Tamsulosin (%)	Placebo (%)
Ejaculatory disorders (Retrograde ejaculation)	14.2–28.1	1.6–2.1	0–1.1
Upper respiratory tract infection	18.9	27.6	19.1
Thirst	10.3	3.6	4.5
Loose stool	9.1	3.6	5.6
Urinary incontinence	6.3	5.7	0
Diarrhea	2.6–6.9	6.8	5.6
Dizziness	3.2–5.1	7.3	4.5
Orthostatic hypotension	2.6	−	1.5
Headache	2.4–5.5	2.9	0.9–4.7
Discontinued the study due to TEAE	2.1–10.7	1.0–5.7	1.6–4.5
Discontinued the study due to ejaculatory disorders	1.3–2.9	0.3	0

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