Transcript Dutasteride – Initial Indian Experience

Dutasteride – Indian Experience
Dr. Sunil Shroff
Professor & HOD, Dept. of Urology & Renal Transplantation
Sri Ramachandra Medical College & Research Institution, Chennai
E-mail: [email protected] or [email protected] www.medindia.net / urology
Dr.Sunil Shroff - Dutasteride 2004
BPH – Changing Patterns in Management
• Over the last 10 years Treatment of BPH has
changed dramatically
• The emphasis is more towards symptom
improvement and prevention of Clinical
progression of BPH
• Medical Treatment with Alpha Blockers and 5Alpha Reductase Inhibitors are now established
alternative to ‘Invasive Therapy’
Dr.Sunil Shroff - Dutasteride 2004
Clinical Progression of BPH
Determines if a patient with BPH develops any
of the below mentioned symptoms on follow up
during watchful waiting Period
 AUR
 Recurrent urinary tract infection or urosepsis,
 Four-point or greater increase in baseline AUA symptom,
 Incontinence
 Need for prostate surgery
 Renal insufficiency due to BPH
Dr.Sunil Shroff - Dutasteride 2004
BPH – Age Related Morbidity
• Among 50 yrs old men, an estimated 35% lifetime
incidence of surgical or medical intervention
• A 60 years old has a 23% chance of experiencing Acute
Urinary Retention if he survives for additional 20 years
• Nearly 1 in 10 men in their 70’s will have Acute Urinary
Retention in the subsequent 5 years
OsterlingJE. Benign prostatic hyperplasia: a review of its histogenesis and natural
history. Prostate Suppl.1996,667-73
Jacobson SJ et al. Natural history of prostatism: risk factors for acute urinary retention.
J Urol. 1997,158:481 -487
Dr.Sunil Shroff - Dutasteride 2004
Reduction in Surgical Treatment
 Decrease in NUMBER of Prostatectomies 1987 ----- 250,000
1996 ----- 116,000
2000 ----- 88,000
 55% Reduction in TURP
 The above decrease may be the result of safer and
better medical therapies
US Health care financing Administration 2000
Dr.Sunil Shroff - Dutasteride 2004
Medical Management of BPH
The effectiveness of alpha-blockers and Androgen
Suppression have validated the Hypothesis that the pathophysiology of BPH comprises of:
- A Dynamic Component - related to prostate smooth muscle
tension (Mechanism of Action for Alpha Blockers)
-
A Static Component - related to prostate size
(Mechanism of Action for 5 Alpha Reductase inhibitors)
Dr.Sunil Shroff - Dutasteride 2004
Does Prostate Volume Reduction Help
•
Prostate Volume does not have strong co-relation to
prostate symptoms
•
However Prostate volume is an important predictor of
risk for developing acute urinary retention (AUR)
•
Finasteride - decreases the risk of progression to
acute urinary retention - benefit greatest in men with
enlarged prostates
Rev Urol. 2003;5(suppl 5):S28-S35]© 2003 Med Reviews
Dr.Sunil Shroff - Dutasteride 2004
 - Blockers – Review of literature
• No long-term data available to prove that alpha blockers
retard or prevent BPH progression
• Limitations
– Elderly age group: Dizziness, Postural Hypotension
– Younger age group: Ejaculatory Dysfunction
• Therapeutic results irrespective of gland size and BOO
• Symptom relief and urodynamic improvement
• Rapid onset of action
Clifford GM et al. Eur Urol 2000;38: 2-19
Dr.Sunil Shroff - Dutasteride 2004
5-Reductase Inhibitors: Review of literature
• Reduce prostate volume
• Reduce risk of progression to AUR
• Reduce risk of prostatic surgery
• Effective for long-term therapies
• Improvement in QoL
Clifford GM et al. Eur Urol 2000;38: 2-19
Dr.Sunil Shroff - Dutasteride 2004
5-Reductase Inhibitors : BPH Progression
Data available from large PLESS (Proscar Long-term Efficacy &
Safety Study) trail with Finasteride showed :
 Improvement in urinary flow (beginning from 4th month)
 Reduction in AUA SI score (by 3.3 vs 1.3 points in
placebo)
 Decreased baseline prostate volume by 18% over
placebo (+14%)
 Reduced PSA levels by half vs those in placebo group
 Reduced risk of AUR & Surgery
PLESS Study – Double Blind and Placebo Controlled Source: McConnel JD
(1998) NEJM
Dr.Sunil Shroff - Dutasteride 2004
Dutasteride – Initial Indian Experience
• Dutasteride - Drug Profile
• Dutasteride – Results of Seven Centres
• Dutasteride – Comparison and Discussion
Testosterone
Dihydrotestosterone
5α-Reductase
DHT is the androgen primarily responsible for the initial development and
subsequent enlargement of the prostate gland.
Dutasteride inhibits the conversion of testosterone to Dihydrotestosterone (DHT)
Dr.Sunil Shroff - Dutasteride 2004
Dutasteride - History of Drug
• Dutasteride – Filed for treatment of BPH in 1995
• Dutasteride Approved by FDA on 20th Nov 2001
• Dutasteride Now available in India – Dr.Reddys
Dr.Sunil Shroff - Dutasteride 2004
Dutasteride – Basis of Trail
The trial designed around the theory that
androgens drive prostate cell growth.
5 - Alpha Reductase Inhibitors meets the two
•key
criteria for a preventive agents:


Non-toxic
Attacks a specific molecular step in the prostatic
tissue to selectively achieve androgen suppression
Testosterone
Dihydrotestosterone
5α-Reductase
Dr.Sunil Shroff - Dutasteride 2004
5α-Reductase
Testosterone is converted to DHT by the enzyme 5α
reductase, which exists as Two Isoforms:
Type I and Type II
– The type I Isoenzyme is also responsible for
testosterone conversion in the Skin and Liver.
– The type II - Isoenzyme is primarily active in the
Reproductive Tissues
Dutasteride a novel dual 5α-Reductase inhibitor
Dr.Sunil Shroff - Dutasteride 2004
Dutasteride – A Novel 5-ARI
• 4- azasteroid
• Selective and potent inhibitor of both type
I & II 5-AR
• Unlike Finasteride, inhibits:
*Type I - 5AR : 45 fold
*Type II -5AR : 2.5 fold
• 5 times more rapid onset of action
Source : Drugs Ageing ( 2003)
Dr.Sunil Shroff - Dutasteride 2004
Dutasteride – Pharmacokinetics
•
•
•
•
•
•
Rapid absorption on oral administration
Tmax
: 1 - 3hrs
Bioavailability
: Approx 60%
Elimination t1/2
: 3-5 weeks
Extensive hepatic metabolism
Faecal excretion
Dr.Sunil Shroff - Dutasteride 2004
Dutasteride on DHT and Testosterone
• Dutasteride showed appreciable reduction in
serum DHT levels, even as early as 1 month
– 1 month
: 87.5%
– 24 months
: 90.2%
• Reductions in DHT are rapid & sustained
• Median increase in Testosterone 19%
(within Physiologic Limits)
Dr.Sunil Shroff - Dutasteride 2004
Inherited Type 2 - 5α-Reductase Deficiency
• Adult males have decreased DHT levels
• 5α-reductase deficient males have a small prostate gland
throughout life and do not develop BPH
• Except for the associated urogenital defects present at
birth, no other clinical abnormalities related to 5αreductase deficiency have been observed in these
individuals.
Dr.Sunil Shroff - Dutasteride 2004
Dutasteride – Effect on PSA Levels
Dutasteride decreased PSA levels in men with BPH
PSA levels at 24 months
Dutasteride (0.5mg/d)
:  50%
Placebo
:  15%
(Ref: Claus GR et al. (2002) Urology 60;434-41)
Claus GR et al. (2002) Urology 60;434-41
Dr.Sunil Shroff - Dutasteride 2004
Dutasteride – Effect on Prostate Volume
Dutasteride decreases both TPV & TZV starting at
1 month and continuing through 24 months
• Significant reduction in both Total Prostate Volume (TPA)
& Transition Zone Volume (TZV)
• Mean % change from baseline:
TPV = -25.7%
TZV = -20.4%
Claus GR et al. (2002) Urology 60;434-41
Dr.Sunil Shroff - Dutasteride 2004
Dutasteride – Effect on Peak Urinary Flow rate (PFR or Qmax)
At 24 months change in Qmax, from baseline:
Dutasteride
Placebo
:
:
+ 2.2 ml/sec
+ 0.9 ml/sec
Claus GR et al. (2002) Urology 60;434-41
Dr.Sunil Shroff - Dutasteride 2004
Dutasteride – Effect on AUR
• Offers 57% risk reduction of AUR
• At 24 months - AUR
• Dutasteride group :
39 (1.8%)
• Placebo group
:
90 (4.2%)
Claus GR et al. (2002) Urology 60;434-41
Dr.Sunil Shroff - Dutasteride 2004
Dutasteride – Special Population
• No dosage adjustment required in elderly &
renal dysfunction
• Cautious use in hepatic dysfunction.
Dr.Sunil Shroff - Dutasteride 2004
Dutasteride – Drug Interactions
• No interaction with :
– 1- adrenoreceptor antagonist
(eg. Tamsulosin, Terazosin)
– Digoxin, warfarin
• Likelihood interactions with :
– Ketoconazole, Verapamil, Diltiazem,
Cimetidine, Ciprofloxacin
Dr.Sunil Shroff - Dutasteride 2004
Metabolism and Elimination
• Dutasteride is extensively metabolized in humans
• Dutasteride and its metabolites are excreted
mainly in feces.
• Only trace amounts of unchanged Dutasteride can
be found in urine (<1%).
Dr.Sunil Shroff - Dutasteride 2004
Dutasteride – Side Effects Profile
Dutasteride • No Effect on Bone density
(52 weeks trail period as measured using DEXA on healthy volunteers)
• The Plasma Lipid Profile was unaffected by Dutasteride
(i.e., total cholesterol, low density lipoproteins, high density
lipoproteins, and triglycerides)
• No clinically significant changes in adrenal hormone
responses to ACTH stimulation were observed in a subset population
(n = 13) of the one-year healthy volunteer study
Dr.Sunil Shroff - Dutasteride 2004
DUTAS (Dutasteride)
The Indian Experience
Dr.Sunil Shroff - Dutasteride 2004
DUTAS (Dutasteride)
An open prospective Phase III study
to evaluate The efficacy & safety of
Dutasteride in men with
Benign Prostatic Hyperplasia (BPH)
Dr.Sunil Shroff - Dutasteride 2004
Clinical Trial Setting
Seven Centres
St.John’s Medical College, Bangalore
Nizam’s Institute of Med Sci., Hyderabad
M.S.Ramaiah Hospital, Bangalore
PSG Institute of Medical Sciences, Coimbatore
Nair Hospital , Mumbai
Sri Ramachandra Medical College ,Chennai
Care Hospital, Hyderabad
After approval of Institutional Ethics Commitee and informed consent
Dr.Sunil Shroff - Dutasteride 2004
Dutas : Bioequivalence Study
• Comparative BE study between Dutas
(DRL) & Avodart caps ( GSK)
• Inference :
* Dutas (DRL) bioequivalent to Avodart .
* Meets International Quality.
Dr.Sunil Shroff - Dutasteride 2004
Dutas : Bioequivalence Study
Mean Serum Concentrations of Dutasteride Vs Time Profile
(n=24)
DRL
Concemtration in ng/mL
7
Avodart
6
5
4
3
2
1
0
0
20
40
60
80
Time in Hours
Dr.Sunil Shroff - Dutasteride 2004
100
120
Prescribing Information : Dutasteride
Composition:
Each soft gelatin capsule contains:
Dutasteride
O.5 mg
Capsules should be swallowed whole
Colour: Iron Oxide Black and Iron Oxide Red
Warnings & Precautions:
• Women who are pregnant or may become pregnant should not
handle Dutasteride capsules because of possible absorption thro’
skin and risk of anomaly to male foetus.
• Caution should be exercised in patients with liver disease
Dr.Sunil Shroff - Dutasteride 2004
Patients Profile on Dutasteride




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
Screened : 234 men with symptoms of BPH
Enrolled : 88 men with BPH fulfilling inclusion criteria
Mean Age = 66.15 yrs
Mean Body Wt. = 64.54 kg
Mean duration of BPH = 2.67 yrs
Dropout: 5
– 4 pts after 4 weeks
– 1pt after 8 weeks
Reason - lost to follow up
Dr.Sunil Shroff - Dutasteride 2004
Dutasteride – Inclusion Profile
 Age 50 years and older
 Clinical diagnosis of BPH based on History,
Physical and DRE
 AUA-SI - of 12 points or more
 Maximum urinary flow rate ( Qmax ) of 15ml / sec or
less
 Voided volume of 125ml or greater
 Prostate volume (TRUS) of 30 cm3 or greater
Inclusion Criteria same as three trials with identical design - Two conducted in the
USA and one in 19 countries.
Dr.Sunil Shroff - Dutasteride 2004
Dutasteride - Exclusion Criteria
Residual volume of greater than 250ml
History of prostate cancer, prior prostate surgery,
Acute urinary retention within 3 months of
screening
Prostate Specific Antigen (PSA) – Normal Range, if
above normal but below 10ng/ml to exclude
malignancy by Sextant Biopsies
Medication history with an α-blocker or other 5αReductase inhibitor in the last four weeks.
Dr.Sunil Shroff - Dutasteride 2004
Evaluation Parameters
 AUA - SI
- ( Week 0, 4, 8 and 12 )
 TPV (TRUS) - ( Week 0, 4 and 12 )
 Qmax
- ( Week 0, 4 and 12 )
 PSA
- ( Week 0 and 12 )
 Clinical Adverse Event - ( Week 0 –12 )
 Hematological and Biochemical Adverse
Events
- ( Week 0 and 12 )
Dr.Sunil Shroff - Dutasteride 2004
DUTAS
Dutasteride
RESULTS
Dr.Sunil Shroff - Dutasteride 2004
AUA-SI
AUA-SI
24
21
20.46
Mean AUA-SI
18
15.06*
15
12.53*
12
9.6*
9
6
3
0
Week 0 [n=86]
*
Week 4 [n=86]
Week 8 [n=69]
Week 12 [n=41]
Significantly different from Week 0, p < 0.00001
Dr.Sunil Shroff - Dutasteride 2004
Total Prostate Volume
Total Prostate Volume
50
45
44.46
39.3*
Mean TPV cm
3
40
35
32.94*
30
25
20
15
10
5
0
Week 0 [n=86]
*
Week 4 [n=83]
Week 12 [n=41]
Significantly different from Week 0, p < 0.00001
Dr.Sunil Shroff - Dutasteride 2004
Maximum Flow Rate
Maximum Flow Rate
Mean Qmax ml/sec
15
12
11.88*
11.94*
10.22
9
6
3
0
Week 0 [n=86]
*
Week 4 [n=86]
Week 12 [n=41]
Significantly different from Week 0, p < 0.0001
Dr.Sunil Shroff - Dutasteride 2004
PSA
Prostate Specific Antigen
3.5
Mean PSA ng/ml
3
2.73
2.5
2
1.63*
1.5
1
0.5
0
Week 0 [n=86]
*
Week 12 [n=41]
Significantly different from Week 0, p < 0.01
Dr.Sunil Shroff - Dutasteride 2004
Dutasteride – SRMC Experience (n 31)
 AUA-SI came down on an average by 7 points
( P value .0001)
 Prostate Volume decrease by 24%
( P value .001)
 Uroflow – mean increase by 3.2 ml/sec
( P value .001)
Dr.Sunil Shroff - Dutasteride 2004
Drug Safety
Seven patients reported adverse events
• Loss of libido (3),
• Erectile dysfunction (3)
• Abdominal pain (1)
• One patient with edema had to discontinue therapy due
to concomitant cardiovascular disorder.
• No significant changes in hematological and
biochemical parameters at week 12 compared to
baseline
Dr.Sunil Shroff - Dutasteride 2004
Finasteride VS Dutasteride
 Finasteride and Dutasteride both Reduce Prostate
Volume
 Both work on Prostate cells and reduce
conversion of Testosterone to DHT by blocking
action of 5α-Reductase
 Finasteride works on 5α-Reductase Isoenzyme
Type II
 Dutasteride exhibit less inter-individual variation in
the level of DHT suppression compared to
Finasteride
Dr.Sunil Shroff - Dutasteride 2004
Combination Therapy in BPH
• Combination therapy with Alpha1 blockers &
5-Reductase Inhibitors may provide > benefit
than mono - Rx
• Rationale :
* alpha blockers offer rapid symptom relief
* 5 – ARIs provide long term risk
reduction
• Above aspects currently evaluated in clinical
trials
Dr.Sunil Shroff - Dutasteride 2004
Dutasteride: Combination Rx with
-adrenergic blockers
Objective
Examine short term combination treatment with 1 – blockers &
Dutasteride
Followed by removal of 1 – blockers and continuation with only
Dutasteride
Trial details
Multicenteric : 32 sites in 6 countries
Age : Men  45years
Methodology 1st Phase: 24 weeks: Combination Rx of Dutasteride 0.5mg/d &
Tamsulosin 0.4 mg/d
2nd Phase: (12 weeks) 50 % of patients on combination & 50% on
Dutasteride mono-Rx
SMART 1
(Symptom Management After Reducing Therapy) : European Urology, 2003
Dr.Sunil Shroff - Dutasteride 2004
SMART – I : Conclusions
• Dutasteride can be used for short-term in
combination Rx with 1-blockers (Tamsulosin)
• Combination Rx achieves rapid symptomatic
relief; maintained even after 1-blockers
withdrawal (after 6 months)
SMART 1 (Symptom Management After Reducing Therapy) : European Urology, 2003
Dr.Sunil Shroff - Dutasteride 2004
Medical therapy: Alone and in combination For BPH
(Final Vs Baseline Comparison Data)
Placebo
Finasteride
Doxazosin
Combination
IPSS
- 5.7
-6.6
-8.3*
-8.5*
PFR (Qmax)
1.4
1.8
3.6*
3.8*
AUR
1.5
1.1
0
0.0
* P < 0.05 vs placebo
Dr.Sunil Shroff - Dutasteride 2004
Dutasteride – Conclusion
• A potent Type I & II - 5--Redutase inhibitor
• Generally well-tolerated
• Safety and tolerability data suggestions that
Dutasteride to be well-tolerated in long-term use.
• Offers rapid onset of action,
• Clinical improvement in symptoms seen
as early as 1 month
• Improves QoL and delays progression of BPH
Dr.Sunil Shroff - Dutasteride 2004
Dutasteride – Conclusion
• 45 and 2.5 times more potent in inhibiting
type I & II – 5 AR respectively than Finasteride
• Can be given effectively in combination with
1 – adrenergic blockers
• Pilot Indian experience in phase 3 trials,
matches with International data.
• Larger multi-centre study can substantiate the
above conclusion in Indian Patients
Dr.Sunil Shroff - Dutasteride 2004
References - Dutasteride
1. OsterlingJE. Benign Prostatic Hyperplasia: A Review of its Histogenesis and Natural History.
Prostate Suppl.1996,667-73
2. Jacobson S J et al. Natural History of Prostatism: Risk Factors for Acute Urinary Retention
3. J Urol. 1997,158:481 -487
4. US Health care Financing Administration 2000
5. Rev Urol. 2003;5 (suppl 5):S28-S35] © 2003 Med Reviews
6. Clifford GM et al. Eur Urol 2000;38: 2-19
7. PLESS Study – Double Blind and Placebo Controlled
8. McConnel JD (1998) NEJM
9. Claus GR et al. (2002) Urology 60;434-41
10. SMART 1 (Symptom Management After Reducing Therapy) : European Urology, 2003
11. PREDICT: Kirby et al J Urol 1999;161;266
Dr.Sunil Shroff - Dutasteride 2004
Dutasteride – Indian Experience
Sunil Shroff
Sri Ramachandra Hospital
Chennai
[email protected]
THANK YOU
Dr.Sunil Shroff - Dutasteride 2004