Dr.Sunil Shroff - Dutasteride 2004 Dutasteride – Indian Experience Dr. Sunil Shroff Professor &...

Dr.Sunil Shroff - Dutasteride 2004

Dutasteride – Indian Experience

Dr. Sunil ShroffProfessor & HOD, Dept. of Urology & Renal TransplantationSri Ramachandra Medical College & Research Institution, Chennai

E-mail: [email protected] or [email protected] www.medindia.net / urology


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’


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


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.1996,667-73Jacobson SJ et al. Natural history of prostatism: risk factors for acute urinary retention. J Urol. 1997,158:481 -487


Reduction in Surgical Treatment

Decrease in NUMBER of Prostatectomies -1987 ----- 250,0001996 ----- 116,0002000 ----- 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


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)


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


- 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


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


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 groupReduced risk of AUR & Surgery

PLESS Study – Double Blind and Placebo Controlled Source: McConnel JD (1998) NEJM


Dutasteride – Initial Indian Experience

• Dutasteride - Drug Profile• Dutasteride – Results of Seven Centres• Dutasteride – Comparison and Discussion

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)

Testosterone Dihydrotestosterone 5α-Reductase


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


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


5α-ReductaseTestosterone 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


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)


Dutasteride – Pharmacokinetics

• Rapid absorption on oral administration • Tmax : 1 - 3hrs

• Bioavailability : Approx 60%• Elimination t1/2 : 3-5 weeks• Extensive hepatic metabolism• Faecal excretion


• 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)

Dutasteride on DHT and Testosterone


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.


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


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


Dutasteride – Effect on Peak Urinary Flow rate (PFR or Qmax)

At 24 months change in Qmax, from baseline:

Dutasteride : + 2.2 ml/sec

Placebo : + 0.9 ml/sec



Dutasteride – Effect on AUR

• Offers 57% risk reduction of AUR• At 24 months - AUR

• Dutasteride group : 39 (1.8%)• Placebo group : 90 (4.2%)



Dutasteride – Special Population

• No dosage adjustment required in elderly & renal dysfunction

• Cautious use in hepatic dysfunction.


Dutasteride – Drug Interactions

• No interaction with : 1- adrenoreceptor antagonist

(eg. Tamsulosin, Terazosin)– Digoxin, warfarin

• Likelihood interactions with :– Ketoconazole, Verapamil, Diltiazem,

Cimetidine, Ciprofloxacin


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%).


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


DUTAS (Dutasteride)

The Indian Experience


An open prospective Phase III study to evaluate The efficacy & safety of

Dutasteride in men with Benign Prostatic Hyperplasia (BPH)

DUTAS (Dutasteride)


Seven CentresSt.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

Clinical Trial Setting

After approval of Institutional Ethics Commitee and informed consent


Dutas : Bioequivalence Study

• Comparative BE study between Dutas (DRL) & Avodart caps ( GSK)

• Inference :

* Dutas (DRL) bioequivalent to Avodart .

* Meets International Quality.


Dutas : Bioequivalence Study

Mean Serum Concentrations of Dutasteride Vs Time Profile (n=24)

0

1

2

3

4

5

6

7

0 20 40 60 80 100 120

Time in Hours

Co

nc

em

tra

tio

n i

n n

g/m

L

DRL

Avodart


Prescribing Information : Dutasteride

Composition:Each soft gelatin capsule contains:

Dutasteride O.5 mg

Capsules should be swallowed wholeColour: 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


Patients Profile on Dutasteride

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


Dutasteride – Inclusion Profile

Age 50 years and olderClinical diagnosis of BPH based on History,

Physical and DREAUA-SI - of 12 points or moreMaximum urinary flow rate ( Qmax ) of 15ml / sec or

less Voided volume of 125ml or greaterProstate 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.


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.


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 )


Dutasteride

RESULTS

DUTAS


AUA-SI

AUA-SI

9.6*

12.53*

20.46

15.06*

0

3

6

9

12

15

18

21

24

Week 0 [n=86] Week 4 [n=86] Week 8 [n=69] Week 12 [n=41]

Mean

AU

A-S

I

* Significantly different from Week 0, p < 0.00001


Total Prostate Volume


Total Prostate Volume

44.46

39.3*

32.94*

0

5

10

15

20

25

30

35

40

45

50

Week 0 [n=86] Week 4 [n=83] Week 12 [n=41]

Mean

TP

V c

m3


Maximum Flow Rate


Maximum Flow Rate

10.22

11.88* 11.94*

0

3

6

9

12

15

Week 0 [n=86] Week 4 [n=86] Week 12 [n=41]

Me

an

Qm

ax

ml/s

ec


PSA


Prostate Specific Antigen

1.63*

2.73

0

0.5

1

1.5

2

2.5

3

3.5

Week 0 [n=86] Week 12 [n=41]

Me

an

PS

A n

g/m

l


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)


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


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


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


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


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


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


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


• 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

Dutasteride – Conclusion


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

References - Dutasteride


Dutasteride – Indian Experience

Sunil ShroffSri Ramachandra Hospital

Chennai

[email protected]

THANK YOU

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