Innovations in Childhood Incontinence: Neurogenic and Functional Bladder Disorders

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1 TNe 10 Innovations in Childhood Incontinence: Neurogenic and Functional Bladder Disorders Stuart B. Bauer, MD President, ICCS Department of Urology Children s Hospital Boston Professor of Urology Harvard Medical School

2 ICCS slide library v Disclaimer These slides are produced by the International Children s Continence Society (ICCS) and may be freely used for educational purposes as long as they are not altered and the source is acknowledged

3 Anticholinergics Alternatives Oxybutynin, tolterodine, trospium, darifenacin, solifenacin propiverine, Effects Antimuscarinic blockade of M 2 & M 3 receptors as well as having a direct detrusor muscle relaxant effect Indications Functional disorders: frequency, urgency, urge incontinence Neurogenic disorders: OAB, poorly compliant bladder Contraindications Residual urine, dry mouth, facial flushing Constipation Δ mental status

4 Anticholinergics Why is one anticholinergic agent effective in one patient and not in another? Why do some patients have intense side effects with the smallest dose possible whereas others have no adverse reaction even after taking much higher than the recommended amount? These phenomena are related to: Conversion from inactive preparatory form to active ingredient Soluability Affinity for specific M end organ receptor Degradation of active metabolite by liver enzymes Rate of excretion of inactive (and active forms) by kidney

5 Anticholinergics Why is one anticholinergic agent effective in one patient and not in another? Why do some patients have intense side effects with the smallest dose possible whereas others have no adverse reaction even after taking much higher than the recommended amount? These phenomena are related to: Conversion from inactive preparatory form to active ingredient Soluability Affinity for specific M end organ receptor Degradation of active metabolite by liver enzymes Rate of excretion of inactive (and active) forms by kidney

6 Pharmacokinetics Area Under the Curve (AUC) & Concentration [C max ] and Terminal half-life (T 1/2 ) are responsible for amount of active drug delivered to the specific end-organ This depends on: Presence of enzymatic activity of cytochrome oxidases Genetic heretogenicity (10% Causcasian. 1% Asian devoid) Renal clearance Liver function Specific drug response to cytochrome degradative enzymes Permeability & effect depends on: Lipophilicity Molecular size Molecular charge Pharmacodynamics

7 Pharmacokinetics AUC [C max ] (T 1/2 ) Effect Antimuscarinic blockade selective for M 3 receptors, which are 1 o responsible for bladder contractility Cytochrome oxidative enzymatic activity (CYP 2D6) Normal esterase activity Increased esterase activity (EM extensive metabolizers) Decreased esterase activity (PM poor metabolizers) Decreased degradative activity (CYP 3A4)

8 Pharmacokinetics AUC [C max ] (T 1/2 ) Effect Antimuscarinic blockade selective for M 3 receptors, which are 1 o responsible for bladder contractility Cytochrome oxidative enzymatic activity (CYP 2D6) Normal esterase activity Increased esterase activity (EM extensive metabolizers) Decreased esterase activity (PM poor metabolizers) Decreased degradative activity (CYP 3A4)

9 Anticholinergics Newest Drugs Fesoterodine Imidafenacin Effect Antimuscarinic blockade selective for M 3 receptors, which are 1 o responsible for bladder contractility Findings Most clinical trials have involved adults with OAB symptoms Few studies on pharmacokinetics and adverse events No studies in children have been reported Results not reported according to ICCS definitions for success / failure

10 Fesoterodine Characteristics Tertiary amine (iso-butyric acid ester) preparation state Active metabolite: 5 hydroxymethyl tolterodine (5-HMT) Conversion to active form by non-specific esterases Tolterodine conversion by CYP 2D6 enzymes (genetic expression) Low lipophilicity & ( + ) charged molecule g i CNS penetration T ½ = 7 9 hrs 70% excreted in urine, 30% metabolized in liver Relative contraindication kidney / liver impairment

11 Fesoterodine Pharmacokinetics Active metabolite: 5-HMT has strong M 3 affinity Breakdown of active drug by CYP 3A4 - as for most antimuscarinics Fesoterodine: h levels 5-HMT in serum vs tolterodine

12 Fesoterodine Study Design Multi-center, RCT, double-blind, placebo vs fesoterodine 4 / 8 mg/day Measured: Δ from baseline (# V mean, UUI, VV mean, # Day V, # Night V, Urge, CD [24h] / week) 735 adults completed 12 week trial - 3 day voiding diary Findings h responses: VV, # dry days / week i voids / 24h, # D & N voids, urge UI Dry mouth: 7, 22 & 34% (placebo, fesoterodine 4, 8 mg) Constipation: 1, 3, & 5% (placebo, fesoterodine 4, 8 mg) Chapple C, et al: Eur Urol, 52; 1204, 2007

13 Fesoterodine Study Design Multi-center, RCT, double-blind, parallel group Subjects divided by: + / - DO on initial UDS Compared placebo vs fesoterodine 4, 8 & 12 mg 210 adults completed 12 weeks trial - 7 day voiding diary (+) DO; 95 (-) DO Measured: Δ voids / 24h, Urge urinary incontinence (UUI) Findings i voids / 24h, UUI that was dose related, irrespective of DO on UDS DO pts had h Vol at 1 st desire, strong desire & mean cystometric cap. Dry mouth & headache: h in fesoterodine vs placebo Nitti V, et al: Brit J Urol, 105; 1268, 2009

14 Fesoterodine Study Design Multi-center, open label, 8-week phase II (safety + pharmacokinetics) Subjects: 21 w NBD [11] + DO / idiopathic DO [10]; age 8 17 yrs Compared: fesoterodine 4, then 8 mg / daily for 4 weeks each Blood samples ([5-HMT] + 3-day voiding diaries at end of weeks 4 & 8 Completed study: 4 mg dose (21); 8 mg dose (20) Findings Similar uptake & degradation of 5-HMT in NBD vs idiopathic DO 5-HMT concentrations were twice the level in 8 vs 4 mg dosing PVR only h (>ICCS def.) 2 pts (>10%) at 8 mg / day dosing SE: slightly greater with higher dose (1 serious [constipation]) Fesoterodine well tolerated in children J Pediatr Urol, 2012

15 Imidafenacin Study Design Long-term phase III prospective trial in 42 adults 0.1 mg / day BID compared to solifenacin 5 mg/day 52 weeks Findings Substantially lower OAB SS & KHQ scores at 52 weeks Lower incidence of dry mouth and constipation than solifenacin (p = 0.04) No significant increase in post-void urine volume M Zaitsu, et al: Kawasaki, Japan, 2011

16 Imidafenacin vs Propiverine Protocol Randomized, double-blind placebo-controlled Phase III trial Design 12 week comparison 3-armed study Imidafenacin (0.1 mg BID) vs propiverine (20 mg / day) vs placebo 7-day voiding diary & King s Health Questionnaire 781 enrolled Imidafenacin (324), propiverine (310), placebo (147) 711 completed - Imidafenacin (301), propiverine (279), placebo (131) Findings: Imidafenacin propiverine placebo (p =< 0.01) Incontinence episodes: i 68% 73% 50% Micturtions / day: i 12% 16% 9% Urgency episodes / day: i 53% 60% 36% Δ Voided volume: h 14% 24% 6% Y Homma & O Yamaguchi: Int J Urol: 16, 499, 2009

17 Protocol Selective Binding (Imidafenacin) on Bladder Muscarinic Receptors Comparison: serum concentrations & binding of imidafenacin vs oxybutynin in rat bladders, salivary glands, colon + other tissues Design Imidafenacin: oral (1.57 & 6.26 µmol/kg) Oxybutynin: oral (76.1 µmol/kg) Sacrificed animals S Yamada, et al: J Pharma Exp Thera: 336, 365, 2011

18 Findings Selective Binding (Imidafenacin) on Bladder Muscarinic Receptors Comparison: serum concentrations & binding of imidafenacin vs oxybutynin in rat bladders, salivary glands, colon + other tissues % binding in tissue S Yamada, et al: J Pharma Exp Thera: 336, 365, 2011

19 Conclusions Selective Binding (Imidafenacin) on Bladder Muscarinic Receptors Imidafenacin binding was significantly lower in the bladder than salivary gland or colon, but greater than in the heart. Bladder & heart has predominantly M 2 with some M 3 receptors whereas salivary glands & colon are primarily M 3. Thus, selective binding is taking place Oral administration time & dose relationship for binding in bladder, salivary gland, heart, colon + lung, but not brain Oral administration g binding in bladder was rapid & long-lasting Overall imidafenacin binds more selectively in bladder than other tissues Oxybutynin binds more significantly to brain receptors than imidafenacin Imidafenacin should be well tolerated for treating OAB S Yamada, et al: J Pharma Exp Thera: 336, 365, 2011

20 Conclusions Both Fesoterodine & Imidafenacin hold promise as potential more effective drugs with fewer side effects than current antimuscarinic drugs available today

21 ICCS slide library v

Anticholinergic medication use for female overactive bladder in the ambulatory setting in the United States.

Página 1 de 6 PubMed darifenacin vs solifenacin Display Settings:, Sorted by Recently Added Results: 5 1. Int Urogynecol J. 2013 Oct 25. [Epub ahead of print] Anticholinergic medication use for female