1. Dutasteride – Indian Experience
Dr. Sunil Shroff
Professor & HOD, Dept. of Urology & Renal Transplantation Sri Ramachandra Medical College & Research Institution, Chennai or / urology
Dr.Sunil Shroff - Dutasteride 2004

2. 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 5-Alpha Reductase Inhibitors are now established alternative to ‘Invasive Therapy’
Dr.Sunil Shroff - Dutasteride 2004

3. 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

4. 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:
Dr.Sunil Shroff - Dutasteride 2004

5. Reduction in Surgical Treatment
Decrease in NUMBER of Prostatectomies -
,000
,000
,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

6. Medical Management of BPH
The effectiveness of alpha-blockers and Androgen
Suppression have validated the Hypothesis that the patho-
physiology 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

7. 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

8.  - 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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 5α-reductase deficiency have been observed in these individuals.
Dr.Sunil Shroff - Dutasteride 2004

19. 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

20. 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

21. Dutasteride – Effect on Peak Urinary Flow rate (PFR or Qmax)
At 24 months change in Qmax, from baseline:
Dutasteride : ml/sec
Placebo : ml/sec
Claus GR et al. (2002) Urology 60;434-41
Dr.Sunil Shroff - Dutasteride 2004

22. 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

23. Dutasteride – Special Population
No dosage adjustment required in elderly & renal dysfunction
Cautious use in hepatic dysfunction.
Dr.Sunil Shroff - Dutasteride 2004

24. 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

25. 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

26. Dutasteride – Side Effects Profile
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

27. Dr.Sunil Shroff - Dutasteride 2004
DUTAS (Dutasteride)
The Indian Experience
Dr.Sunil Shroff - Dutasteride 2004

28. 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

29. 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

30. Dutas : Bioequivalence Study Dr.Sunil Shroff - Dutasteride 2004
Comparative BE study between Dutas (DRL) & Avodart caps ( GSK)
Inference :
* Dutas (DRL) bioequivalent to Avodart .
* Meets International Quality.
Dr.Sunil Shroff - Dutasteride 2004

31. Dutas : Bioequivalence Study Dr.Sunil Shroff - Dutasteride 2004

32. Dr.Sunil Shroff - Dutasteride 2004
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

33. Patients Profile on Dutasteride Dr.Sunil Shroff - Dutasteride 2004
Screened : 234 men with symptoms of BPH
Enrolled : 88 men with BPH fulfilling inclusion criteria
Mean Age = yrs
Mean Body Wt. = 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

34. 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

35. 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 5α-Reductase inhibitor in the last four weeks.
Dr.Sunil Shroff - Dutasteride 2004

36. Evaluation Parameters Dr.Sunil Shroff - Dutasteride 2004
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

37. Dr.Sunil Shroff - Dutasteride 2004
RESULTS
Dr.Sunil Shroff - Dutasteride 2004

38. Dr.Sunil Shroff - Dutasteride 2004
AUA-SI
* Significantly different from Week 0, p <
Dr.Sunil Shroff - Dutasteride 2004

39. Dr.Sunil Shroff - Dutasteride 2004
Total Prostate Volume
* Significantly different from Week 0, p <
Dr.Sunil Shroff - Dutasteride 2004

40. Dr.Sunil Shroff - Dutasteride 2004
Maximum Flow Rate
* Significantly different from Week 0, p <
Dr.Sunil Shroff - Dutasteride 2004

41. Dr.Sunil Shroff - Dutasteride 2004
PSA
* Significantly different from Week 0, p < 0.01
Dr.Sunil Shroff - Dutasteride 2004

42. 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
Dr.Sunil Shroff - Dutasteride 2004

43. 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

44. 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

45. 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

46. 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

47. 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

48. 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
* P < 0.05 vs placebo
Dr.Sunil Shroff - Dutasteride 2004

49. Dutasteride – Conclusion Dr.Sunil Shroff - Dutasteride 2004
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

50. 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

51. 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:
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

52. Dutasteride – Indian Experience
Sunil Shroff
Sri Ramachandra Hospital
Chennai
THANK YOU
Dr.Sunil Shroff - Dutasteride 2004