Transcript α 1B - SwopInfo

SILODOSIN:
THE DIFFERENTIAL EFFECTS OF A
NOVEL ALPHA BLOCKER
What we have learned about LUTS….
1.
2.
3.
4.
5.
It is a multifactorial disease
It has a complex pathophisiology
We have predictive factors available
There are 3 types of symptoms
Not all patients should be treated with the same
drugs
6. New drug therapies
7. New surgical options
2
EAU Guidelines on the Treatment of
Male Non-neurogenic LUTS
LUTS
MILD LUTS
MODERATE LUTS SEVERE LUTS
(IPSS <8)
(IPSS 8 – 19)
(IPSS ≥20)
WACHTFUL
WAITING
MEDICAL
THERAPY
MEDICAL/
SURGICAL
THERAPY
EAU , 2014: http: /www.uroweb.org
AUA ,2010:http://www.aua.net.org/ NICE , 2010:http://www.guidance.nice.org.ukdeline
CCurrently available drugs for LUTS
• α-blockers
• 5-ARIs
• Anticholinergics
• β3- adrenergics
• PDE5-I
• Combinations
– α-blockers + 5-ARIs
– α-blockers + Anticolinergics
4
CHOOSING TREATMENT:
Categorize patients according to symptoms.
Asses predictive factors of progression.
Set the goals of therapy.
Discuss adverse effects
5
Available α- blockers
•
•
•
•
•
Doxazosine
Terazosine
Alfuzosine
Tamsulosine
Silodosine
Quick symptoms relief
WHY SILODOSIN …?
WHY SILODOSIN – the 3S
1. Selectivity
2. Sustained efficacy
3. Safety
α1 Adrenoreceptor Distribution & Function
1.
2.
3.
4.
α1A
α1B
α1D
Primary subtype expressed
in the prostate. Regulates
contraction of the smooth
muscle in the prostate,
bladder base and neck,
urethra, seminal vesicles,
and vas deferens.1-5
Primary subtype expressed
in the blood vessels.
Regulates contraction of
arterial blood vessels in
response to postural
redistribution of blood
volume.4-7
Primary subtype expressed
in the bladder, spinal cord,
and nasal passages.
Thought to play a role in
bladder symptoms and nasal
secretions.1,6
Schwinn DA, et al. Int J Urol. 2008;15:193-199.
Kaplan SA. Urology. 2004;63:428-434.
Nasu K, et al. Br J Pharmacol. 1996;119:797-803.
Murata S, et al. J Urol. 2000;164:578-583.
5. Carbone DJ, et al. Int J Impotence Res. 2003;15:299-306.
6. Stafford-Smith M, et al. Can J Anesth. 2007;54:549-555.
7. Townsend SA, et al. Hypertension. 2004;44:776-782.
Pharmacologic Selectivity Profiles
of α1-Blockers
α1-Blocker
α1-Receptor Selectivity
 Doxazosin1
α1A = α1D = α1B
 Terazosin1
α1A = α1D = α1B
 Alfuzosin1
α1A = α1D = α1B
 Tamsulosin1,2
α1A = α1D >α1B
 Silodosin3
α1A >α1D >α1B
Results based on in vitro data
1. Schwinn DA, et al. Mayo Clin Proc. 2004;79:1423-1434.
2. Kenny BA, et al. Br J Pharmacol. 1996;118:871-878.
3. Akiyama K, et al. J Pharm Exp Ther. 1999;291:81-91.
α1-Blocker Selectivity Profiles
Receptor
Selectivity
α1-Blocker

α1A:α1B

Silodosin

162:1

Tamsulosin

10:1

Alfuzosin

1:1
Results based on in vitro studies
IN VITRO DIFFERENCES IN ALPHA-BLOCKER SELECTIVITY MAY NOT
CORRELATE TO DIFFERENCES IN ACTUAL CLINICAL OUTCOMES.
Ratio expressed as the relative concentration.
Tatemichi S, et al. Yakugaku Zasshi. 2006;12:209-216.
Data on file, Watson Laboratories, Inc. KMD-0005 Study Report.
α1A Adrenoreceptor Expression
Increases in BPH vs Non-BPH Prostate Tissue
Non-BPH Tissue
BPH Tissue
α1A
63%
85%
α1D
31%
14%
α1B
6%
1%
Nasu K, et al. Br J Pharmacol. 1996;119:797-803.
α1B Adrenoreceptor Expression
in the Vasculature Increases with Age
Adrenoreceptor
Expression
Rudner XL, et al. Circulation. 1999;100:2336-2343.
•Age <55 years
•Age ≥65 years
• α1A>α1B
• α1B>α1A
Silodosin is tissue-selective
Silodosin reduces phenylephrine-contraction of the rabbit
prostate at low concentrations with a “window” to effects on
the aorta
Yamagishi et al Eur J Pharmacol 315;73, 1996
Akiyama et al., JPET 291;81, 1999
Akiyama et al Int J Urol 8; 177, 2001
Silodosin exhibits functional selectivity
dog
rat
Silodosin reduces rat or dog urethral pressure in vivo at doses
that have little effect on blood pressure
Yamagishi et al Eur J Pharmacol 315;73, 1996
Akiyama et al., JPET 291;81, 1999
Akiyama et al Int J Urol 8; 177, 2001
SILODOSIN: A Uniquely Selective Alpha-Blocker
 Highly receptor-subtype selective
– Binds with much higher affinity to α1A receptors than α1D or
α1B receptors in in vitro studies
 Highly tissue selective
– Silodosin has ~200 times higher affinity for prostatic tissue
than aortic tissue
Shibata K, et al. Mol Pharmacol. 1995;48:250-258.
SILODOSIN – the 3S
1. Selectivity
2. Sustained efficacy
3. Safety
Silodosin is efficacious within 2 - 6 hours…
…..with sustained efficacy during 12-weeks treatment (8mg o.d) versus
placebo (p<0.0001 – p<0.005) in two phase III trials in the USA
Marks et al J Urol 181, 2634, 2009
SILODOSIN: Combined IPSS Subscale Analysis
Week 12†
Week 0.5 (Day 3 or 4)
Change From Baseline (mean ± SEM)
IPSS
IPSS Storage
IPSS
Voiding
IPSS
0
0
-1
-1
-2
-3
-5
*
-3
*
*
-4
*
-5
-6
-6
-7
-7
-8
-8
*
*P≤0.0002
based on last observation carried forward. IPSS, International Prostate Symptom Score.
Marks LS, et al. J Urol. 2009;181:2634-2640.
†Analysis
IPSS
Voiding
-2
*
-4
IPSS Storage
Silodosin
Placebo
Silodosin and tamsulosin: comparison in the subgroup
of patients with nocturia (IPSS) at baseline
*Statistically significant superiority vs placebo in patients
with at least 2 episodes of nocturia at baseline (not for tamsulosin)
Chapple et al, Eur Urol, 2011
Montorsi F, Eur Urol Suppl 2010
Schneider et al – World J Urol – in press
Simultaneous improvement in symptoms
Statistically significant
superiority vs tamsulosin on
simultaneous improvement of
frequency, nocturia and
incomplete emptying
(EU study - post hoc analysis)
Montorsi F., Eur. Urol. Suppl. 2010; 9: 491-495.
% of patients with a simultaneous improvement
in 3 of the most bothersome symptoms
SILODOSIN: EFFICACY
Changes in Urodynamic Parameters Before and at 3 Months After
Silodosin Treatment
•Before (n=35)
•After (n=29)
•P valuesa
•First desire to void (ml)
•193.1± 105.5
•230.3± 99.9
•0.0974
•Maximum cystometric capacity (ml)
•356.1± 139.6
•409.1± 122.2
•0.0027
•40.5± 51.9
•45.0 ±34.2
•0.3806
•Before (n=23)
•After (n=20)
•P valuesa
•85.3± 35.3
•37.4± 42.9
•0.0003
•Bladder volume at FIC (ml)c
•285.34 ±112.8
•380.6± 136.87
•0.0003
•Pressure flow study
•Before (n=35)
•After (n=27)
•P valuesa
•Detrusor opening pressure (cm H2O)
•77.8± 42.9
•52.2± 20.7
•0.0010
•Detrusor pressure at Qmax
•80.6± 37.8
•48.6 ±25.3
•<0.0001
•Bladder outlet obstruction index
•70.2 ±38.1
•32.6 ±29.2
•<0.0001
•Schäfer’s linear passive urethral resistance relation obstruction
class
•4.5 ±1.5
•2.6 ±1.5
•<0.0001
•Watts factor at Qmax (µW/mm2)
•9.9 ±6.6
•8.8 ±6.0
•0.7784
•Bladder compliance (ml/cm H2O)
•Detrusor overactivity (DO)
•Amplitude of the largest DO contraction (cm H2O)b
• Statistically significant improvement of almost all urodynamic parameters
• - 44% of the patients avoided invasive surgery, due to the improvement of
LUTS obtained with silodosin
Yamanishi et. al, Neurourol. Urodynam. 29:558–562, 2010
SILODOSIN – the 3S
1. Selectivity
2. Sustained efficacy
3. Safety
Silodosin has no effect on ECG parameters
Heart Rate
QTc interval
Time-averaged change (beats / min)
10
5
placebo
0
Silodosin 8 mg od
Silodosin 24 mg od
-5
-10
In 139 healthy male subjects, placebo, silodosin 8 or 24 mg once daily for 5
days did not affect heart rate, QTc interval, PR-interval or QRS-complex and
did not cause any deviations of the ECG morphology
Morganroth et al Clin Pharm Ther 87, 609, 2010
Safety data
• At normal (8mg) and supra-therapeutic (24mg) doses no
meaningful effects on heart rate, PR and QRS interval duration
(study S105014)
• Does not affect cardiac repolarization
MacDiarmid et al Urology 75;l, 520-25, 2010
Silodosin exhibits cardiovascular safety in efficacy trials
80
160
Heart-rate
Systolic BP
100
Diastolic BP
140
40
100
mmHg
mmHg
beats / min
80
120
60
80
60
40
20
60
placebo
40
Silodosin 8 mg od
20
20
0
baseline
endpoint
0
0
baseline
endpoint
baseline
endpoint
Silodosin is similar to findings
with placebo reported with low
frequencies of cardiovascular
adverse events
*Data from Kawabe et al BJU Int 2006
§No episodes to orthostatic test. Chapple et al Eur Urol 2011.
Kawabe et al. Marks et al BJU Int98, 1019, 2006
Marks et al. J Urol 181, 2634, 2009
Chapple et al Eur Urol 59, 342, 2011
Supine blood pressure
Montorsi F., Eur. Urol. Suppl. 2010; 9: 491-495
Low Incidence of Orthostatic
Hypotension in All Age Groups
Age Group
No. of
Patients
Incidence of
Orthostatic
Hypotension
•<65 years
259
2.3%
≥65 years
207
2.9%
≥75 years
 60
5.0%
All patients
466
2.6%
RAPAFLO® (silodosin) Capsules full Prescribing Information. November 2009.
Silodosin lacks clinically relevant interaction with sildenafil or
tadalafil
Heart-rate
MacDiarmid et al Urology 75;l, 520, 2010
Systolic BP
Diastolic BP
SILODOSIN: SAFETY & TOLERABILITY
Most common adverse reactions (all studies)
•Placebo controlled studies
•Preferred Term
•All studies
•Silodosin 8mg
•(n=931)
•Placebo
•(n=733)
•Silodosin
•(n=1,581)
•Total No. of patients with
drug related AE
•268 (28.8%)
•66 (9.0%)
•502 (31.8%)
•Retrograde ejaculation
•200 (21.5%)
•6 (0.8%)
•373 (23.6%)
•Dizziness
•17 (1.8%)
•6 (0.8%)
•33 (2.1%)
•Orthostatic hypotension
•11 (1.2%)
•6 (0.8%)
•20 (1.3%)
•Nasal Congestion
•9 (1.0%)
•1 (0.1%)
•20 (1.3%)
•Headache
•10 (1.1%)
•9 (1.2%)
•20 (1.3%)
•Diarrhoea
•6 (0.6%)
•2 (0.3%)
•16 (1.0%)
Data on File, Recordati- Summary of safety; Capitanio et al: Int.J.Clin.Pract. E-publ.doi:10/1111/ijcp.12135, 2013
SILODOSIN: SAFETY & TOLERABILITY
Discontinuations due to adverse reactions
• In controlled studies 40/931 (4.3%) patients discontinued with
silodosin, as compared to 14/733 (1.9%) patients on placebo
• Overall (controlled + long term extension), only 148/1,581 (9.4%)
subjects discontinued the study due to TEAE
• The most frequent cause was retrograde ejaculation (3.9%)
• Dizziness was a cause of discontinuation in 8/1,581 patients (0.5%)
• Orthostatic hypotension in only 3/1,581 patients (0.2%)
Data on File, Recordati- Summary of safety; Capitanio et al : Int.J.Clin.Pract.,e-publ. doi:10.1111/ijcp.12135, 2013
Understanding Retrograde Ejaculation
 Orgasm with reduced or no semen
 Due to reduced contraction of smooth muscles
of vas deferens and seminal vesicles, mediated
via α1A receptor1-4
– Expected side effect of α1A-selective antagonists
 Not true RE but reduced seminal expulsion2
 Not a serious side effect
 Reversible on discontinuation5
1.
2.
3.
4.
5.
Hisasue S, et al. Int J Urol. 2006;13:1311-1316.
Noguchi Y, et al. Eur J Pharmacol. 2008;580:256-261.
Kobayashi K, et al. J Sex Med. 2008;5:2185-2190.
Moriyama N, et al. Br J Pharmacol. 1997;122:1009-1041.
RAPAFLO® (silodosin) Capsules full Prescribing Information, November 2009.
SILODOSIN: EFFICACY & SAFETY
Change from baseline (IPSS)
-0
***
-5
Placebo
No-EjD
Sil-EjD
***
†
*
**
†††
-10
**
††
†††
†††
-15
Pre-dose
1
2
4
8
12
LOCF
Observation period (week)
• Ejaculation disorder was associated with a significantly improved
change in total IPSS at all time points from weeks 1-12 vs no
ejaculation disorder or placebo
Homma Urology76:1446 2010
Silodosin Post-hoc Responder Analysis
by Ejaculation Status
40
Placebo (n=457)
No RE (n=335)
RE (n=131)
34.4
35
Percent
30
27.5
23
25
20.9
20
12.9
15
10
9.2
5
0
≥30% IPSS and Qmax
≥3 Units IPSS and Qmax
 RE associated with improvement in IPSS response with silodosin
RE= retrograde ejaculation
Roehrborn et al,Prost.Ca.Prost.Dis.2011:143-8.
CONCLUSIONS - Selectivity, Sustained
efficacy and Safety (1)
• Highly selective α1A-adrenoreceptor antagonist
• Significantly more effective than placebo and at least as
effective as tamsulosin (0.4 mg once a day) in improving
IPSS score, storage sub-score and voiding sub-score
• Post-hoc analyses have shown that is significantly more
efficacious than tamsulosin in improving the triad of
symptoms including incomplete emptying, frequency and
nocturia
CONCLUSIONS - Selectivity, Sustained
efficacy and Safety (2)
• Minimal cardiovascular effects
• The most common adverse reaction is retrograde
ejaculation (drug discontinuation only in less than 4% of
patients)
• Can co prescribe silodosin and PDE-5 inhibitors
1
Categorize patients according to symptoms
Nocturia as main complaint
2
Asses predictive factors of progression
Prostate <30-40 gr; PSA< 1.5
3
Set the goals of therapy
Quick improvement of symptoms
41
Discuss adverse effects
Avoidance of CV effects; Not-ejaculation focused
38
Nocturia main complaint
39