Beyond the Abstract - Use of mirabegron in treating overactive bladder, by G. Alessandro Digesu, MD

BERKELEY, CA (UroToday.com) - β-1, 2 and 3 adrenoreceptors have been recently confirmed in human urothelium and detrusor muscle.[1] It has been shown that stimulation of human β-2 and β-3 adrenoreceptors results in direct relaxation of detrusor smooth muscle via activation of G proteins and adenyl cyclase, which increases the levels of cyclic AMP. It is thought that the β 3 adrenoreceptor subtype predominantly mediates human bladder smooth muscle relaxation[2-4] and they have been proposed as a potential target to treat OAB symptoms. Mirabegron is an orally active selective β 3 adrenoreceptor agonist which has been widely studied in animals where it has been shown to decrease the frequency of rhythmic bladder contractions during the filling phase without suppressing the amplitude of bladder contraction during micturition.[5]

"The published evidence appears to favour mirabegron as a new effective and well-tolerated class of drug for patients with OAB symptoms. However, in comparison to antimuscarinics, only a relatively small number of patients have been studied so far. Although long-term data are still pending, mirabegron can be considered an attractive alternative to antimuscarinics."

Pharmacodynamics

Mirabegron is a lipophilic compound that undergoes hepatic metabolism. It acts as a substrate and it is metabolised by cytochrome P450 3A4 (CYP3A4) and 2D6 (CYP2D6). CYP2D6 shows phenotypical variability due to genetic polymorphism; thus a particular subject may be described as either a poor or an extensive metaboliser. The incidence of poor metaboliser phenotypes in Caucasians is approximately 5-10%. Van Gelderen et al.[6] compared single dose pharmacokinetics of mirabegron in CYP2D6 poor and extensive metabolisers (PM and EM). Results showed that the percentage of the dose excreted unchanged in the urine was higher in PMs (15.4+/-4.2%) compared with EMs (11.7+/-3.0%). Mirabegron was studied in patients with mild, moderate, and severe renal impairment (NCT00750620; 178-CL-038). Tmax was similar in EMs and PMs and its respective half-life was 23 and 25 hours. Mean Cmax and mean AUC were slightly higher in PMs compared to EMs.

Clinical Efficacy

A Phase IIa dose finding study [7] (multicentre, randomised, double-blind, parallel group, proof of concept study) evaluated the efficacy of YM178 compared with placebo and tolterodine. Two hundred sixty patients were enrolled into a single-blind 2 week placebo run-in period after which they were randomised to 4 groups; placebo (n=66), mirabegron 100mg twice daily (n=65), mirabegron 150mg twice daily (n=65), and tolterodine 4mg once daily (n=64) for a 4-week period. Both doses of mirabegron showed a statistically significant reduction of mean micturition frequency by 17% and 18% at 100 and 150mg of mirabegron, respectively, compared to 9% for placebo and 11% for tolterodine.

A following Phase IIB trial was a dose ranging study [8] carried out in Europe aiming to determine the efficacy and safety of mirabegron once daily in patients with OAB. A total of 919 patients were randomly assigned to five groups: placebo, mirabegron 25mg, 50mg, 100mg, and 200mg for a 12-week period. Analysis showed statistically significant dose-dependent reductions in mean number of micturitions per 24 hours for mirabegron 50, 100, and 200mg group compared to placebo (-2.1, -2.1 and -2.2, respectively, p<0.05). It was also seen that mirabegron caused a dose-dependent increase in mean urine volume voided in each micturition compared with placebo (27.3, 25.6 and 33.3 for 50, 100, and 200mg, respectively, p<0.05).

Khullar et al.[9] conducted a phase III multicentre, randomised, double-blind, parallel-group, placebo and active controlled trial in Europe and Australia and reported on the efficacy and tolerability data for mirabegron in patients with OAB. Patients with OAB were enrolled into a 2-week placebo run and then randomised to receive either placebo, mirabegron 50mg, mirabegron 100mg, or extended release tolterodine 4mg once daily for 4 weeks. A total of 1978 patients were randomised. Results showed both mirabegron groups to have a statistically significant reduction in number of incontinence episodes/24h (-1.57 for 50mg, -1.46 for 100mg) and number of micturitions/24h (-1.93, -1.77, respectively) from baseline compared to placebo.

Phase III data from North America again looked at efficacy and tolerability.[10] This was a 12-week, multicenter, randomized, double-blind, parallel-group, placebo-controlled trial with patients receiving either placebo, 50, or 100mg of mirabegron. 1328 patients were included. Similar results were seen with both mirabegron groups showing statistically significant improvement in the number of incontinence episodes in 24 hours (-1.13, -1.47 and -1.63 for placebo, mirabegron 50mg, and 100mg, respectively, p<0.05) and in the number of micturitions in 24 hours (-1.05, -1.66 and -1.75 for placebo, mirabegron 50mg, and 100mg, respectively p<0.05). Statistically significant improvements were evident at the first measured time point (Week 4) for incontinence episodes and micturitions.

The results of these phase III trials are encouraging towards mirabegron having a role in the pharmacological management of OAB. Results are awaited from further phase III trials investigating effects of long-term mirabegron use in OAB (52 weeks) (NCT00688688).

Safety and Tolerability

In the BLOSSOM proof-of-concept study [7] the incidence of adverse effects was 39.2% compared with 36.4% for the placebo group and 48.4% in the tolterodine group. The most common side effect reported with mirabegron in this study was headache (6.9%) and gastrointestinal upset (13.8%) but this was lower than tolterodine (9.4% and 23.4%, respectively).

The DRAGON study [8] assessed safety of mirabegron at 4 different doses (25, 50,100, and 200mg). The incidence of 1 or more treatment-emergent adverse events in the mirabegron groups was between 43.8-47.9% compared with 43.2% in the placebo group. The most common adverse events in the mirabegron groups were infections and infestations (14.1%) as well as gastrointestinal disorders (12.1%). Higher doses of mirabegron (100 and 200mg) were associated with a mean increase in heart rate from baseline of 1.6 to 4.1 beats per minute but this was not associated with increased incidence of cardiovascular adverse events. There was also a less than 1.5mmHg change in blood pressure from baseline in the mirabegron group compared to placebo.

The European-Australian study [9] showed a similar incidence of adverse events. The overall adverse events reported was 43.3%, 46.7%, 42.8%, and 40.1%, for the placebo, tolterodine slow release, mirabegron 50 and 100mg groups, respectively. The incidence of hypertension was 7.7%, 8.1%, 5.9%, and 5.4%, dry mouth 2.6%, 10.1%, 2.8%, and 2.8%; headache was 2.8%, 3.6%, 3.7%, and 1.8% for the above stated groups, respectively.

Data from the North American phase III trial [10]showed the overall adverse events reported was 50.1%, 51.6%, and 46.9% across the placebo, mirabegron 50 and 100 mg groups, respectively. The incidence of hypertension was 6.6%, 6.1%, and 4.9% whereas headache was 2.0%, 3.2%, and 3.0% across the placebo, mirabegron 50 and 100 mg groups, respectively.

Special Populations and Drug Interactions

A phase I open label crossover study evaluated the effect of multiple doses of mirabegron on desipramine metabolism, a tricyclic antidepressant and CYP2D6 substrate.[11] Twenty-eight healthy subjects (14 male and 14 female) who were all genotyped as extensive CYP2D6 metabolisers received a single dose of desipramine 50mg on days 1, 18, and 38 in addition to mirabegron 100 mg from day 5 to day 23. The study reported that the combination of mirabegron resulted in a longer half life of desipramine with a 1.8 increase in Cmax and 3.4 fold increase in AUC.

Veltkamp et al.[12] carried out a phase I trial looking at potential drug interactions between mirabegron and metformin. Results showed no clinically relevant pharmacokinectic, pharmacodynamics, or safety interactions and the authors concluded that mirabegron can be used safely in type 2 diabetes patients treated with metformin. Further phase I studies looking at interactions between mirabegron and rifampicin, warfarin, and the oral contraceptive pill are awaited.

Conclusion

The published evidence appears to favour mirabegron as a new effective and well-tolerated class of drug for patients with OAB symptoms. However, in comparison to antimuscarinics, only a relatively small number of patients have been studied so far. Although long-term data are still pending, mirabegron can be considered an attractive alternative to antimuscarinics.

References:

  1. Tyagi P, Thomas CA, Yoshimura N, Chancellor MB 2009 Investigations into the presence of functional Beta1, Beta2 and Beta3-adrenoceptors in urothelium and detrusor of human bladder. Int Braz J Urol 35(1):76-83.
  2. Takeda M, Obara K, Mizusawa T, Tomita Y, Arai K, Tsutsui T, et al. 1999. Evidence for beta3-adrenoceptor subtypes in relaxation of the human urinary bladder detrusor: analysis by molecular biological and pharmacological methods. J Pharmacol Exp Ther 288(3):1367-73.
  3. Takeda H, Yamazaki Y, Akahane M, Igawa Y, Ajisawa Y, Nishizawa O 2000. Role of the beta(3)-adrenoceptor in urine storage in the rat: comparison between the selective beta(3)-adrenoceptor agonist, CL316, 243, and various smooth muscle relaxants. J Pharmacol Exp Ther 293(3):939-45.
  4. Igawa Y, Aizawa N, Homma Y 2010. Beta3-adrenoceptor agonists: possible role in the treatment of overactive bladder. Korean J Urol 51(12):811-8.
  5. 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(2):642-7.
  6. van Gelderen EM, Li Q, Meijer J 2009. An exploratory comparison of the single dose pharmacokinetics of the beta 3-adrenoceptor agonist mirabegron in healthy CYP2D6 poor and extensive metabolizers. Clinical Phamacol Ther 85 (suppl 1):S88.
  7. Chapple CR, Yamaguchi O, Ridder A, Liehne J, Carl S, Mattiasson A, et al. 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(3):239.
  8. Chapple C, Wyndaele JJ, Van Kerrebroeck P, Radziszewski P, Dvorak V, Boerrigter P 2010. Dose-ranging study of once-daily mirabegron (YM178), a novel selective 3-adrenoceptor agonist, in patients with overactive bladder (OAB). Eur Urol Suppl 9(2):249.
  9. Khullar V, Cambronero J, Stroberg P, Angulo J, Boerrigter P, Blauwet MB, et al. 2011. The efficacy and tolerability of mirabegron in patients with overactive bladder-results from a European-Australian Phase III trial. Eur Urol Suppl 10(2):278-279
  10. Nitti V, Herschorn S, Auerbach S, Ayers M, Lee M, Martin N 2011. The Selective [beta] 3-adrenoreceptor agonist mirabegron is effective and well tolerated in pateints with overactive bladder syndrome. Journal of Urology 185(4):e783-e784.
  11. W.J.Krauwinkel, van Gelderen EM, Groen MJ 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. American Society for Clinical Pharmacolgy and Therapeutics Annual Meeting Abs PIII-65.
  12. Veltkamp S, van Gelderen M, Schaddelee M 2009. Clinical study into the pharmacokinetic, pharmacodynamic and safety interaction of the novel b3-adrenoreceptor agonist mirabegron and metformin in healthy subjects. Basic & Clinical Pharmacology & Toxicology 105 (Suppl):146.

 


 Written by:

G. Alessandro Digesu, MD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract. 


 

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