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Time to Onset of Improvement in Symptoms of OAB

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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Time to Onset of Improvement in Symptoms of OAB

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  1. Delbert Rudy, M.D. North Texas Clinical Research, Urology Associates of North Texas Arlington, Texas Time to Onset of Improvement in Symptoms of OAB

  2. Definition: Time To Onset of Action The simple pharmacokinetic “serum levels” or something more complicated? First notice or separation from placebo?

  3. 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

  4. 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)

  5. 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)

  6. 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

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. 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.

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