delbert rudy m d north texas clinical research urology associates of north texas arlington texas n.
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Delbert Rudy, M.D. North Texas Clinical Research, Urology Associates of North Texas Arlington, Texas . Time to Onset of Improvement in Symptoms of OAB. Definition: Time To Onset of Action. The simple pharmacokinetic “serum levels” or something more complicated?.

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delbert rudy m d north texas clinical research urology associates of north texas arlington texas
Delbert Rudy, M.D.

North Texas Clinical Research,

Urology Associates of North Texas

Arlington, Texas

Time to Onset of Improvement in Symptoms of OAB

definition time to onset of action
Definition: Time To Onset of Action

The simple pharmacokinetic “serum levels” or something more complicated?

First notice or separation from placebo?

how do we measure time to onset of improvement
How Do We Measure Time to Onset of Improvement?

Steady state serum levels versus symptom assessment

Methods

Symptom Assessment

  • Patient diary
  • Physician/patient interview
  • Physician documentation
  • Patient awareness
  • Score or scale
  • Metrics
  • Efficacy
  • Urgency
  • Incontinence episodes
  • Frequency of voids
  • Voided volume
  • Tolerability
  • Dry mouth
  • Constipation
  • Blurry vision
  • CNS related side-effects
  • Safety
pharmacokinetics with repeated dosing

2

1

0

1

2

3

4

5

6

Pharmacokinetics With Repeated Dosing
  • Steady State
  • Attained after approximately four half-times
  • Time to steady state independent of dosage
  • Fluctuations
  • Proportional to dosage interval/half-time
  • Blunted by slow absorption
  • Steady-state Concentrations
  • Proportional to dose/dosage interval
  • Proportional to CL/F

Time (multiples of elimination half-time)

pharmacokinetics of antimuscarinic agents

Trospium Chloride 18 hours

Tolterodine-IR 2 hours

Tolterodine-ER 8 hours

Oxybutynin-IR 2 - 3 hours

Oxybutynin Transdermal 7 – 8 hours*

Oxybutynin XL 12 – 13 hours

Darifenacin 12-19 hours

Solifenacin 50 hours

Pharmacokinetics of Antimuscarinic Agents

Enablex PI (Novartis), Ditropan XL PI (Orth McNeil), Vesicare PI (Astellas), Sanctura PI (Esprit Pharma), Detrol IR PI (Pfizer)

studies assessing time to onset of improvement in symptoms of oab

Study: Solifenacin vs. Placebo2

Symptoms: Urgency episodes; nocturia episodes; micturition frequency; mean volume voids

Methods: Micturition diary

Efficacy Records: 4, 8, 12 weeks

Study: Darifenacin vs. Placebo3

Symptoms: Incontinence episodes, frequency and severity of urgency, voiding frequency, volume voided

Methods: Electronic patient diary

Efficacy Records: 12 weeks

Study: Tolderodine ER vs Placebo4

Symptoms: Urgency episodes, incontinence episodes, micturition frequency

Methods: Micturition diary and measures of patients’/physicians’ perceptions of improvement

Efficacy Records: 1, 4, 12 weeks

Studies Assessing Time to Onset of Improvement in Symptoms of OAB

Study: OPERA: Oxybutynin ER vs Tolterodine ER1

Symptoms: UUI episodes; total incontinence; micturition frequency

Methods: Urinary diary

Efficacy Records: 4, 8, 12 weeks

OAB therapies have been proven effective in improving OAB symptoms, but what is the time of onset of action?

1.Diokno et al..Mayo Clin Proc. 2003.Jun;78(6):687-95. 2.Cardozo et al. J of Urol. (2004); 172:1919-19243 Chapple et al. BJU Int. 2005 May;95(7):993-10014 Siami et al clinical therapeutics 2002 (24) 616-628

only trospium chlpride has looked to onset of action in the first week
Only trospium chlpride has looked to onset of action in the first week

Objective

Evaluate time to onset of statistically significant and clinically meaningful effects of trospium chloride in patients with overactive bladder

OXYBUTININ VS. TOLTERODINE

SOLIFENACIN

DARIFENACIN

TOLDERODINE

TROSPIUM

TROSPIUM

Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Week 2

Week 4

Week 6

Week 8

Week 10

Week 12

Rudy D. BJUInternational. 2006;97:540-546.

time to onset of improvement in symptoms of oab using antimuscarinic treatment
Time to Onset of Improvement in Symptoms of OAB Using Antimuscarinic Treatment

Patient Disposition

Patient calls received (n = 10060)

Patient referred to sites (n = 3718)

Screen failures

(n = 1601)

(percentages are approximate)

Urinary frequency average 14%

Not intereseted 16%

Other medical reasons 15%

Urge incontinence average 9%

Total daily volume 6%

Not predominately urge incontinence 9%

Not willing to consent 5%

Unable to complete urinary diary correctly 6%

Other 20%

Screened patients (n = 2259)

Randomized patients (n = 658)

Placebo (n = 329)

Trospium chloride (n = 329)

Patients completed (n = 297)

Early withdrawal (n = 32)

Patients completed (n = 287)

Early withdrawal (n = 42)

Adverse event (n = 32)

Withdrew consent (n = 8)

Non-compliance (n = 4)

Lost to follow-up (n = 3)

Other (n = 1)

Adverse event (n = 25)

Withdrew consent (n = 10)

Non-compliance (n = 2)

Lost to follow-up (n = 5)

Rudy D. BJUInternational. 2006;97:540-546.

mean change from baseline in toilet voids day
Mean Change from Baseline in Toilet Voids/Day

Week 1 Day 1

Week 1Day 2

Week 1Day 3

Week 1 Day 4

Week 1 Day 5

Week 1 Day 6

Week 1 Day 7

Week 4

Week 12

Mean change in toilet voids from baseline

*

*

*

*

*

Weekly data (Weeks 4 and 12) are average findings across 7 days of diary data

* P-value for treatment comparability statistically significant.

Rudy D. BJUInternational. 2006;97:540-546.

median change from baseline in uui episodes day
Median Change from Baseline in UUI Episodes/Day

Week 1 Day 1

Week 1Day 2

Week 1Day 3

Week 1 Day 4

Week 1 Day 5

Week 1 Day 6

Week 1 Day 7

Week 4

Week 12

*

Mean change in UUI from baseline

*

*

*

*

*

*

*

*

Weekly data (Weeks 4 and 12) are average findings across 7 days of diary data

* P-value for treatment comparability statistically significant.

Rudy D. BJUInternational. 2006;97:540-546.

median change from baseline in urgency severity
Median Change from Baseline in Urgency Severity

Week 1 Day 6

Week 1 Day 7

Week 1Day 2

Week 1Day 3

Week 1 Day 4

Week 1 Day 5

Week 4

Week 12

Week 1 Day 1

Mean change in urgency severityfrom baseline

*

*

*

*

*

*

** P-value for treatment comparability statistically significant

Weekly data (Weeks 4 and 12) are average findings across 7 days of diary data.

Note: The trospium chloride group exhibited no change from baseline on Day 1, and thus no bar is presented.

*

Rudy D. BJUInternational. 2006;97:540-546.

median oab scs change from baseline
Median OAB-SCS Change from Baseline

Week 1 Day 1

Week 1Day 2

Week 1Day 3

Week 1 Day 4

Week 1 Day 5

Week 1 Day 6

Week 1 Day 7

*

Mean change in urgency severity from baseline

*

*

*

*

*

*

Weekly data (Weeks 4 and 12) are average findings across 7 days of diary data

* P-value for treatment comparability statistically significant.

Rudy D. BJUInternational. 2006;97:540-546.

time to onset of improvement in symptoms of oab using antimuscarinic treatment1
Time to Onset of Improvement in Symptoms of OAB Using Antimuscarinic Treatment
  • Trospium chloride demonstrated statistically significant improvements in efficacy over placebo within a few days of treatment, with improvements in symptoms continuing to 7 days of treatment in endpoints:
    • toilet voids
    • urgency severity/void
    • UUI episodes
    • OAB-SCS
  • Clinically meaningful improvements in many endpoints by the end of the first week

Rudy D. BJUInternational. 2006;97:540-546.

conclusions
Conclusions
  • Rapid onset of effect should be encouraging but not definitive
  • Full treatment effect should be expected to take several weeks, perhaps even more than 12

#13

only trospium chlpride has looked to onset of action in the first week1
Only trospium chlpride has looked to onset of action in the first week

Objective

Evaluate time to onset of statistically significant and clinically meaningful effects of trospium chloride in patients with overactive bladder

OXYBUTININ VS. TOLTERODINE

SOLIFENACIN

DARIFENACIN

TOLDERODINE

TROSPIUM

TROSPIUM

Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Week 2

Week 4

Week 6

Week 8

Week 10

Week 12

Rudy D. BJUInternational. 2006;97:540-546.