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Published in: International Urogynecology Journal 2/2014

01-02-2014 | Review Article

What do we know and not know about mirabegron, a novel β3 agonist, in the treatment of overactive bladder?

Authors: Romain Caremel, Oleg Loutochin, Jacques Corcos

Published in: International Urogynecology Journal | Issue 2/2014

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Abstract

Introduction and hypothesis

Mirabegron is a novel β3-adrenoceptor agonist recently approved by Japanese, American, and European authorities for overactive bladder (OAB) therapy. Here we review existing knowledge on this new class of medication, analyze existing literature on the topic, and make recommendations regarding its administration and necessary future studies.

Methods

We reviewed the current literature and analyzed mirabegron efficacy, safety, and suitability for treating OAB symptoms. We performed a systematic search of Medline/PubMed, and Embase. Studies exploring mechanisms involved in the effects of mirabegron were included. Searches were limited to the English language.

Results

Two phase II and two large-scale phase III multinational randomized controlled trials have supported mirabegron efficacy and tolerability with up to 12 weeks of therapy in OAB patients. The reported frequency and severity of treatment-emergent and serious adverse events were similar to antimuscarinics but with more than threefold lower incidence of dry mouth than with tolterodine. However, effects on the cardiovascular system, cognitive functions, pharmacokinetic interactions with other drugs, and long-term adverse events have not yet been fully investigated.

Conclusion

Anticholinergic drugs should remain the first-line pharmacologic treatment for OAB until head-to-head comparative study eventually shows that mirabegron has equivalent or superior efficacy. However, it seems logical to use mirabegron as second-line treatment of OAB in patients who are poor responders or intolerant to anticholinergics.
Literature
1.
go back to reference Haylen BT, de Ridder D, Freeman RM, Swift SE, Berghmans B, Lee J, Monga A, Petri E, Rizk DE, Sand PK, Schaer GN (2010) An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Int Urogynecol J 21(1):5–26PubMedCrossRef Haylen BT, de Ridder D, Freeman RM, Swift SE, Berghmans B, Lee J, Monga A, Petri E, Rizk DE, Sand PK, Schaer GN (2010) An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Int Urogynecol J 21(1):5–26PubMedCrossRef
2.
go back to reference Irwin DE, Milsom I, Hunskaar S, Coyne K, Kelleher C, Hampel C et al (2006) Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol 50:1306–1314PubMedCrossRef Irwin DE, Milsom I, Hunskaar S, Coyne K, Kelleher C, Hampel C et al (2006) Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol 50:1306–1314PubMedCrossRef
3.
go back to reference Coyne KS, Sexton CC, Kopp ZS, Ebel-Bitoun C, Milsom I, Chapple C (2011) The impact of overactive bladder on mental health, work productivity and health-related quality of life in the UK and Sweden: results from EpiLUTS. BJU Int 108:1459–1471PubMedCrossRef Coyne KS, Sexton CC, Kopp ZS, Ebel-Bitoun C, Milsom I, Chapple C (2011) The impact of overactive bladder on mental health, work productivity and health-related quality of life in the UK and Sweden: results from EpiLUTS. BJU Int 108:1459–1471PubMedCrossRef
4.
go back to reference Murphy AM, Krlin RM, Goldman HB (2013) Treatment of overactive bladder: what is on the horizon? Int Urogynecol J 24(1):5–13PubMedCrossRef Murphy AM, Krlin RM, Goldman HB (2013) Treatment of overactive bladder: what is on the horizon? Int Urogynecol J 24(1):5–13PubMedCrossRef
5.
go back to reference Andersson KE (1993) Pharmacology of lower urinary tract smooth muscles and penile erectile tissues. Pharmacol Rev 45:253–308 Andersson KE (1993) Pharmacology of lower urinary tract smooth muscles and penile erectile tissues. Pharmacol Rev 45:253–308
6.
go back to reference Michel MC, Vrydag W (2006) Alpha1-, alpha2- and beta-adrenoceptors in the urinary bladder, urethra and prostate. Br J Pharmacol 147(Suppl 2):S88–S119PubMedCrossRef Michel MC, Vrydag W (2006) Alpha1-, alpha2- and beta-adrenoceptors in the urinary bladder, urethra and prostate. Br J Pharmacol 147(Suppl 2):S88–S119PubMedCrossRef
7.
go back to reference Andersson KE, Arner A (2004) Urinary bladder contraction and relaxation: physiology and pathophysiology. Physiol Rev 84:935–986PubMedCrossRef Andersson KE, Arner A (2004) Urinary bladder contraction and relaxation: physiology and pathophysiology. Physiol Rev 84:935–986PubMedCrossRef
8.
go back to reference Otsuka A, Shinbo H, Matsumoto R, Kurita Y, Ozono S (2008) Expression and functional role of beta-adrenoceptors in the human urinary bladder urothelium. Naunyn Schmiedebergs Arch Pharmacol 377:473–481PubMedCrossRef Otsuka A, Shinbo H, Matsumoto R, Kurita Y, Ozono S (2008) Expression and functional role of beta-adrenoceptors in the human urinary bladder urothelium. Naunyn Schmiedebergs Arch Pharmacol 377:473–481PubMedCrossRef
9.
go back to reference Igawa Y, Yamazaki Y, Takeda H et al (1999) Functional and molecular biological evidence for a possible beta3-adrenoceptor in the human detrusor muscle. Br J Pharmacol 126:819–825PubMedCrossRef Igawa Y, Yamazaki Y, Takeda H et al (1999) Functional and molecular biological evidence for a possible beta3-adrenoceptor in the human detrusor muscle. Br J Pharmacol 126:819–825PubMedCrossRef
10.
go back to reference Badawi JK, Seja T, Uecelehan H, Honeck P, Kwon ST, Bross S et al (2007) Relaxation of human detrusor muscle by selective beta-2 and beta-3 agonists and endogenous catecholamines. Urology 69:785–790PubMedCrossRef Badawi JK, Seja T, Uecelehan H, Honeck P, Kwon ST, Bross S et al (2007) Relaxation of human detrusor muscle by selective beta-2 and beta-3 agonists and endogenous catecholamines. Urology 69:785–790PubMedCrossRef
11.
go back to reference Leon LA, Hoffman BE, Gardner SD, Laping NJ, Evans C, Lashinger ES et al (2008) Effects of the beta 3-adrenergic receptor agonist disodium 5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl],3-benzodioxole-2,2-dicarboxylate (CL-316243) on bladder micturition reflex in spontaneously hypertensive rats. J Pharmacol Exp Ther 326:178–185PubMedCrossRef Leon LA, Hoffman BE, Gardner SD, Laping NJ, Evans C, Lashinger ES et al (2008) Effects of the beta 3-adrenergic receptor agonist disodium 5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl],3-benzodioxole-2,2-dicarboxylate (CL-316243) on bladder micturition reflex in spontaneously hypertensive rats. J Pharmacol Exp Ther 326:178–185PubMedCrossRef
12.
go back to reference Uchida H, Shishido K, Nomiya M, Yamaguchi O (2005) Involvement of cyclic AMP-dependent and -independent mechanisms in the relaxation of rat detrusor muscle via beta-adrenoceptors. Eur J Pharmacol 518:195–202PubMedCrossRef Uchida H, Shishido K, Nomiya M, Yamaguchi O (2005) Involvement of cyclic AMP-dependent and -independent mechanisms in the relaxation of rat detrusor muscle via beta-adrenoceptors. Eur J Pharmacol 518:195–202PubMedCrossRef
13.
go back to reference Frazier EP, Peters SL, Braverman AS, Ruggieri MR Sr, Michel MC (2008) Signal transduction underlying the control of urinary bladder smooth muscle tone by muscarinic receptors and beta-adrenoceptors. Naunyn Schmiedebergs Arch Pharmacol 377:449–462PubMedCentralPubMedCrossRef Frazier EP, Peters SL, Braverman AS, Ruggieri MR Sr, Michel MC (2008) Signal transduction underlying the control of urinary bladder smooth muscle tone by muscarinic receptors and beta-adrenoceptors. Naunyn Schmiedebergs Arch Pharmacol 377:449–462PubMedCentralPubMedCrossRef
14.
go back to reference Takemoto J, Masumiya H, Nunoki K, Sato T, Nakagawa H, Ikeda Y et al (2008) Potentiation of potassium currents by beta-adrenoceptor agonists in human urinary bladder smooth muscle cells: a possible electrical mechanism of relaxation. Pharmacology 81:251–258PubMedCrossRef Takemoto J, Masumiya H, Nunoki K, Sato T, Nakagawa H, Ikeda Y et al (2008) Potentiation of potassium currents by beta-adrenoceptor agonists in human urinary bladder smooth muscle cells: a possible electrical mechanism of relaxation. Pharmacology 81:251–258PubMedCrossRef
15.
go back to reference Hristov KL, Cui X, Brown SM, Liu L, Kellett WF, Petkov GV et al (2008) Stimulation of beta3-adrenoceptors relaxes rat urinary bladder smooth muscle via activation of the large-conductance Ca2+ − activated K+ channels. Am J Physiol Cell Physiol 295:1344–1353CrossRef Hristov KL, Cui X, Brown SM, Liu L, Kellett WF, Petkov GV et al (2008) Stimulation of beta3-adrenoceptors relaxes rat urinary bladder smooth muscle via activation of the large-conductance Ca2+ − activated K+ channels. Am J Physiol Cell Physiol 295:1344–1353CrossRef
16.
go back to reference Takasu T, Ukai M, Sato S, Matsui T, Nagase I, Maruyama T et al (2007) Effect of (R)-[2-(2-aminothiazol-4-yl)-4′-2-[(2 hydroxy-2-phenylethyl)-amino]ethyl] acetanilide (YM178), a novel selective beta3 adrenoceptor agonist, on bladder function. J Pharmacol Exp Ther 321:642–647PubMedCrossRef Takasu T, Ukai M, Sato S, Matsui T, Nagase I, Maruyama T et al (2007) Effect of (R)-[2-(2-aminothiazol-4-yl)-4′-2-[(2 hydroxy-2-phenylethyl)-amino]ethyl] acetanilide (YM178), a novel selective beta3 adrenoceptor agonist, on bladder function. J Pharmacol Exp Ther 321:642–647PubMedCrossRef
17.
go back to reference Noguchi Y, Someya A, Ukai M (2009) Effects of mirabegron (YM178) on non-micturition contractions in the bladder of conscious rats with bladder outlet obstruction (BOO). J Urol [proceedings of Annual Meeting of the American Urological Association (AUA) (April 25–30, 2009, Chicago)] 181(4, Suppl.): Abstract 25 Noguchi Y, Someya A, Ukai M (2009) Effects of mirabegron (YM178) on non-micturition contractions in the bladder of conscious rats with bladder outlet obstruction (BOO). J Urol [proceedings of Annual Meeting of the American Urological Association (AUA) (April 25–30, 2009, Chicago)] 181(4, Suppl.): Abstract 25
18.
go back to reference Gillespie J, Guilloteau V, Korstanje C, Lluel P, Palea S (2012) Modulation of non-voiding activity by the muscarinergic antagonist tolterodine and the β(3)-adrenoceptor agonist mirabegron in conscious rats with partial outflow obstruction. BJU Int 110(2 Pt 2):E132–E142PubMedCrossRef Gillespie J, Guilloteau V, Korstanje C, Lluel P, Palea S (2012) Modulation of non-voiding activity by the muscarinergic antagonist tolterodine and the β(3)-adrenoceptor agonist mirabegron in conscious rats with partial outflow obstruction. BJU Int 110(2 Pt 2):E132–E142PubMedCrossRef
19.
go back to reference Someya A, Ukai M, Yanai H (2010) Mirabegron (YM178), a novel beta3-adrenoceptor (AR) agonist, increased functional bladder capacity and decreased micturition frequency in conscious water-loaded cynomolgus monkeys. Eur Urol Suppl [Proceedings of 25th Congress of the European Association of Urologists (April 16–20, 2010, Barcelona)] 9(2): Abstract 266 Someya A, Ukai M, Yanai H (2010) Mirabegron (YM178), a novel beta3-adrenoceptor (AR) agonist, increased functional bladder capacity and decreased micturition frequency in conscious water-loaded cynomolgus monkeys. Eur Urol Suppl [Proceedings of 25th Congress of the European Association of Urologists (April 16–20, 2010, Barcelona)] 9(2): Abstract 266
20.
go back to reference Hicks A, McCafferty GP, Riedel E, Aiyar N, Pullen M, Evans C et al (2007) GW427353 (solabegron), a novel, selective beta3-adrenergic receptor agonist, evokes bladder relaxation and increases micturition reflex threshold in the dog. J Pharmacol Exp Ther 323:202–209PubMedCrossRef Hicks A, McCafferty GP, Riedel E, Aiyar N, Pullen M, Evans C et al (2007) GW427353 (solabegron), a novel, selective beta3-adrenergic receptor agonist, evokes bladder relaxation and increases micturition reflex threshold in the dog. J Pharmacol Exp Ther 323:202–209PubMedCrossRef
21.
go back to reference Aizawa N, Homma Y, Igawa Y (2011) Effects of mirabegron (YM178), a novel beta3-adrenoceptor agonist, on the primary bladder afferent activity of the rat. Neurourol Urodyn [Proceedings of 41st Annual Meeting of the International Continence Society (August 29-September 2, 2011, Glasgow)] 30(6): Abstract 154 Aizawa N, Homma Y, Igawa Y (2011) Effects of mirabegron (YM178), a novel beta3-adrenoceptor agonist, on the primary bladder afferent activity of the rat. Neurourol Urodyn [Proceedings of 41st Annual Meeting of the International Continence Society (August 29-September 2, 2011, Glasgow)] 30(6): Abstract 154
22.
go back to reference Ursino MG, Vasina V, Raschi E, Crema F, De Ponti F (2009) The beta3-adrenoceptor as a therapeutic target: current perspectives. Pharmacol Res 59:221–234PubMedCrossRef Ursino MG, Vasina V, Raschi E, Crema F, De Ponti F (2009) The beta3-adrenoceptor as a therapeutic target: current perspectives. Pharmacol Res 59:221–234PubMedCrossRef
23.
24.
go back to reference Honda K, Nomiya M, Shishido K (2006) Mutation of beta3-adrenocepor gene: a genetic marker for overactive bladder. Neurourol Urodyn 25(suppl):652 Honda K, Nomiya M, Shishido K (2006) Mutation of beta3-adrenocepor gene: a genetic marker for overactive bladder. Neurourol Urodyn 25(suppl):652
25.
go back to reference Krauwinkel WJ, van Gelderen EM, Groen MJ, Schaddelee M, de Koning P (2010) An open-label, one-sequence crossover study to evaluate the effect of multiple doses of mirabegron on the pharmacokinetics of the CYP2D6 substrate desipramine in healthy subjects. Clin Pharmacol Ther [Proceedings of 111st Annual Meeting of the American Society of Clinical Pharmacology and Therapeutics (ASCPT) (March 17–20,Atlanta)]; 87(Suppl. 1): Abstract PIII-65 Krauwinkel WJ, van Gelderen EM, Groen MJ, Schaddelee M, de Koning P (2010) An open-label, one-sequence crossover study to evaluate the effect of multiple doses of mirabegron on the pharmacokinetics of the CYP2D6 substrate desipramine in healthy subjects. Clin Pharmacol Ther [Proceedings of 111st Annual Meeting of the American Society of Clinical Pharmacology and Therapeutics (ASCPT) (March 17–20,Atlanta)]; 87(Suppl. 1): Abstract PIII-65
26.
go back to reference Veltkamp S, Gelderen M, Schaddelee M, Krauwinkel W, Koning P (2009) Clinical study into the pharmacokinetic, pharmacodynamic and safety interaction of the novel beta3-adrenoceptor agonist mirabegron and metformin in healthy subjects. Basic Clin Pharmacol Toxicol [Proceedings of 9th Congress of the European Association of Clinical Pharmacology and Therapeutics (EACPT) (July 12–15, 2009, Edinburgh)]; 105(Suppl. 1): Abstract WP107 Veltkamp S, Gelderen M, Schaddelee M, Krauwinkel W, Koning P (2009) Clinical study into the pharmacokinetic, pharmacodynamic and safety interaction of the novel beta3-adrenoceptor agonist mirabegron and metformin in healthy subjects. Basic Clin Pharmacol Toxicol [Proceedings of 9th Congress of the European Association of Clinical Pharmacology and Therapeutics (EACPT) (July 12–15, 2009, Edinburgh)]; 105(Suppl. 1): Abstract WP107
27.
go back to reference Sawamoto T, Lee J, Alak A (2011) Phase I, open-label, drug interaction study to evaluate the effect of multiple doses of ketoconazole on single dose mirabegron (YM178) oral controlled absorption system (OCAS) in healthy adult subjects. Clin Pharmacol Ther [112th Annual Meeting of the American Society of Clinical Pharmacology and Therapeutics (March 2–5, 2011, Dallas)]; 89(Suppl. 1): Abstract PI-43 Sawamoto T, Lee J, Alak A (2011) Phase I, open-label, drug interaction study to evaluate the effect of multiple doses of ketoconazole on single dose mirabegron (YM178) oral controlled absorption system (OCAS) in healthy adult subjects. Clin Pharmacol Ther [112th Annual Meeting of the American Society of Clinical Pharmacology and Therapeutics (March 2–5, 2011, Dallas)]; 89(Suppl. 1): Abstract PI-43
28.
go back to reference Sawamoto T, Lee J, Cao Y (2011) Phase I, open-label, drug interaction study to evaluate the effect of repeat doses of rifampin on the single-dose pharmacokinetics of mirabegron (YM178) in healthy adult subjects. Clin Pharmacol Ther [Proceedings of 112th Annual Meeting of the American Society of Clinical Pharmacology and Therapeutics (March 2–5, 2011, Dallas)]; 89(Suppl. 1): Abstract PI-44 Sawamoto T, Lee J, Cao Y (2011) Phase I, open-label, drug interaction study to evaluate the effect of repeat doses of rifampin on the single-dose pharmacokinetics of mirabegron (YM178) in healthy adult subjects. Clin Pharmacol Ther [Proceedings of 112th Annual Meeting of the American Society of Clinical Pharmacology and Therapeutics (March 2–5, 2011, Dallas)]; 89(Suppl. 1): Abstract PI-44
29.
go back to reference Chapple C, Dvorak V, Radziszewski P, Van Kerrebroeck P, Wyndaele JJ, Bosman B, Boerrigter P, Drogendijk T, ridder A, Van Der Putten-Slob I, Yamaguchi O, on behalf of the Dragon Investigator Group (2013) A phase II dose-ranging study of mirabegron in patients with overactive bladder. Int Urogynecol J. Mars 8 (Epub ahead of print) Chapple C, Dvorak V, Radziszewski P, Van Kerrebroeck P, Wyndaele JJ, Bosman B, Boerrigter P, Drogendijk T, ridder A, Van Der Putten-Slob I, Yamaguchi O, on behalf of the Dragon Investigator Group (2013) A phase II dose-ranging study of mirabegron in patients with overactive bladder. Int Urogynecol J. Mars 8 (Epub ahead of print)
30.
go back to reference Khullar V, Amarenco G, Angulo JC, Cambronero J, Hoye K, Milson I et al (2013) Efficacy and tolerability of mirabegron, a β(3)-adrenoceptor agonist, in patients with overactive bladder: results from a European-Australian phase III trial. Euro Urol 63:283–295CrossRef Khullar V, Amarenco G, Angulo JC, Cambronero J, Hoye K, Milson I et al (2013) Efficacy and tolerability of mirabegron, a β(3)-adrenoceptor agonist, in patients with overactive bladder: results from a European-Australian phase III trial. Euro Urol 63:283–295CrossRef
31.
go back to reference Nitti VW, Auerbach S, Martin N, Calhoun A, Lee M, Herschorn S (2012) Results of a randomized phase III trial of Mirabegron in patients with overactive bladder. J Urol. doi:10.1016/j.juro.2012.10.017 [Epub ahead of print] Nitti VW, Auerbach S, Martin N, Calhoun A, Lee M, Herschorn S (2012) Results of a randomized phase III trial of Mirabegron in patients with overactive bladder. J Urol. doi:10.​1016/​j.​juro.​2012.​10.​017 [Epub ahead of print]
32.
go back to reference Chapple CR, Yamaguchi O, Ridder A (2008) Clinical proof of concept study (Blossom) shows novel 3 adrenoceptor agonist YM178 is effective and well tolerated in the treatment of symptoms of overactive bladder. Eur Urol Suppl 7:239 Chapple CR, Yamaguchi O, Ridder A (2008) Clinical proof of concept study (Blossom) shows novel 3 adrenoceptor agonist YM178 is effective and well tolerated in the treatment of symptoms of overactive bladder. Eur Urol Suppl 7:239
33.
go back to reference Andersson KE, Olsgansky B (2007) Treating patients with overactive bladder syndrome with antimuscarinics: heart rate considerations. BJU Int 100:1000–1014 Andersson KE, Olsgansky B (2007) Treating patients with overactive bladder syndrome with antimuscarinics: heart rate considerations. BJU Int 100:1000–1014
34.
go back to reference Martin N (2012) Randomised, double-blind, placebo-controlled study to assess the ocular safety of mirabegron in normotensive IOP research subjects. Proceedings of European Urology Association Annual Conference; Paris; Poster AM12-1928: 686 Martin N (2012) Randomised, double-blind, placebo-controlled study to assess the ocular safety of mirabegron in normotensive IOP research subjects. Proceedings of European Urology Association Annual Conference; Paris; Poster AM12-1928: 686
35.
go back to reference Chancellor M, Boone T (2012) Anticholinergics for overactive bladder therapy: central nervous system effects. CNS Neurosci Ther 18:167–174PubMedCrossRef Chancellor M, Boone T (2012) Anticholinergics for overactive bladder therapy: central nervous system effects. CNS Neurosci Ther 18:167–174PubMedCrossRef
36.
go back to reference Rodriguez M, Carillon C, Coquerel A, Le Fur G, Ferrara P, Caput D et al (1995) Evidence for the presence of beta 3-adrenergic receptor mRNA in the human brain. Brain Res Mol Brain Res 29:369–375PubMedCrossRef Rodriguez M, Carillon C, Coquerel A, Le Fur G, Ferrara P, Caput D et al (1995) Evidence for the presence of beta 3-adrenergic receptor mRNA in the human brain. Brain Res Mol Brain Res 29:369–375PubMedCrossRef
37.
go back to reference Athanaspoulos A, Chapple C, Fowler C, Gratzke C, Kaplan S, Stief C et al (2011) The role of antimuscarinics in the management of men with symptoms of overactive bladder associated with concomitant bladder outlet obstruction: an update. Eur Urol 60:94–105CrossRef Athanaspoulos A, Chapple C, Fowler C, Gratzke C, Kaplan S, Stief C et al (2011) The role of antimuscarinics in the management of men with symptoms of overactive bladder associated with concomitant bladder outlet obstruction: an update. Eur Urol 60:94–105CrossRef
38.
go back to reference Bhide AA, Digesu GA, Fernando R, Khullar V (2012) Use of mirabegron in treating overactive bladder. Int Urogynecol J 23(10):1345–1348PubMedCrossRef Bhide AA, Digesu GA, Fernando R, Khullar V (2012) Use of mirabegron in treating overactive bladder. Int Urogynecol J 23(10):1345–1348PubMedCrossRef
Metadata
Title
What do we know and not know about mirabegron, a novel β3 agonist, in the treatment of overactive bladder?
Authors
Romain Caremel
Oleg Loutochin
Jacques Corcos
Publication date
01-02-2014
Publisher
Springer London
Published in
International Urogynecology Journal / Issue 2/2014
Print ISSN: 0937-3462
Electronic ISSN: 1433-3023
DOI
https://doi.org/10.1007/s00192-013-2161-4

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