Abstract
Mirabegron is a potent and selective β3-adrenoceptor agonist developed for the treatment of overactive bladder. In vitro studies demonstrated that mirabegron partly acts as a (quasi-) irreversible, metabolism-dependent inhibitor of CYP2D6. The effect of steady-state mirabegron on single doses of the sensitive CYP2D6 substrates metoprolol (100 mg) and desipramine (50 mg) was assessed in two open-label, one-sequence crossover studies in healthy subjects (CYP2D6 extensive metabolizers). Mirabegron 160 mg/day increased metoprolol maximum plasma concentration (C max) 1.90-fold (90 % confidence interval [CI] 1.54; 2.33) and total exposure (AUC0-∞) 3.29-fold (90 % CI 2.70; 4.00) in 12 males (study 1). Mean metoprolol half-life increased from 2.96 to 4.11 h. α-Hydroxymetoprolol C max and AUC to last measurable concentration decreased 2.6-fold and 2.2-fold, respectively. In study 2, mirabegron 100 mg/day increased desipramine C max 1.79-fold (90 % CI 1.69; 1.90) and AUC0-∞ 3.41-fold (90 % CI 3.07; 3.80) in 14 males and 14 females. Mean desipramine half-life increased from 19.5 to 35.8 h. C max of 2-hydroxydesipramine decreased ~twofold, while AUC increased ~1.3-fold. Desipramine was administered again 2 weeks after the last mirabegron dose. Desipramine C max and AUC0-∞ were still ~1.13-fold increased; the 90 % CIs fell within the 0.80–1.25 interval. All treatments were well tolerated. In conclusion, mirabegron is a moderate CYP2D6 inhibitor (ratio and 90 % CI <5.0).
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Aarnoutse RE, Kleinnijenhuis J, Koopmans PP, Touw D, Wieling J, Hekster YA, Burger DM (2005) Effect of low-dose ritonavir (100 mg twice daily) on the activity of cytochrome P450 2D6 in healthy volunteers. Clin Pharmacol Ther 78:664–674
Alderman J, Preskorn SH, Greenblatt DJ, Harrison W, Penenberg D, Allison J, Chung M (1997) Desipramine pharmacokinetics when coadministered with paroxetine or sertraline in extensive metabolizers. J Clin Psychopharmacol 17:284–291
Eltink C, Lee J, Schaddelee MP, Zhang W, Meijer J, van Marle S, Grunenberg N (2012) Single dose pharmacokinetics and absolute bioavailability of mirabegron, a selective and potent β3-adrenoceptor agonist for treatment of overactive bladder. Int J Clin Pharmacol Ther 50:838–850
European Medicines Agency (2010) Draft Guideline on the Investigation of Drug Interactions. http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/05/WC500090112.pdf. Accessed 28 January 2013
Evert B, Griese EU, Eichelbaum M (1994) Cloning and sequencing of a new non-functional CYP2D6 allele: deletion of T1795 in exon 3 generates a premature stop codon. Pharmacogenetics 4:271–274
Gueorguieva I, Jackson K, Wrighton SA, Sinha VP, Chien JY (2010) Desipramine, substrate for CYP2D6 activity: population pharmacokinetic model and design elements of drug–drug interaction trials. Br J Clin Pharmacol 70:523–536
Hamelin BA, Bouayad A, Méthot J, Jobin J, Desgagnés P, Poirier P, Allaire J (2000) Significant interaction between the nonprescription antihistamine diphenhydramine and the CYP2D6 substrate metoprolol in healthy men with high or low CYP2D6 activity. Clin Pharmacol Ther 67:466–477
Harris RZ, Salfi M, Posvar E, Hoelscher D, Padhi D (2007) Pharmacokinetics of desipramine HCl when administered with cinacalcet HCl. Eur J Clin Pharmacol 63:159–163
Heim M, Meyer UA (1990) Genotyping of poor metabolisers of debrisoquine by allele-specific PCR amplification. Lancet 336:529–532
Hemeryck A, Lefebvre RA, De Vriendt C, Belpaire FM (2000) Paroxetine affects metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers. Clin Pharmacol Ther 67:283–291
Johansson I, Lundqvist E, Dahl ML, Ingelman-Sundberg M (1996) PCR-based genotyping for duplicated and deleted CYP2D6 genes. Pharmacogenetics 6:351–355
Khullar V, Amarenco G, Angulo JC, Cambronero J, Hoye K, Milsom I, Radziszewski P, Rechberger T, Boerrigter P, Drogendijk T, Wooning M, Chapple C (2013) Efficacy and tolerability of mirabegron, a beta(3)-adrenoceptor agonist, in patients with overactive bladder: results from a Randomised European-Australian Phase 3 Trial. Eur Urol 63:283–295. doi:10.1016/j.eururo.2012.10.016
Laine K, De Bruyn S, Björklund H, Rouru J, Hänninen J, Scheinin H, Anttila M (2004) Effect of the novel anxiolytic drug deramciclane on cytochrome P(450) 2D6 activity as measured by desipramine pharmacokinetics. Eur J Clin Pharmacol 59:893–898
Lee J, Moy S, Meijer J, Krauwinkel W, Sawamoto T, Kerbusch V, Kowalski D, Roy M, Marion A, Takusagawa S, van Gelderen M, Keirns J. Role of Cytochrome P450 Isoenzymes 3A and 2D6 in the in Vivo Metabolism of Mirabegron, a β3-adrenoceptor agonist. Clin Drug Invest. 2013 (Accepted)
Lennard MS, Tucker GT, Silas JH, Woods HF (1986) Debrisoquine polymorphism and the metabolism and action of metoprolol, timolol, propranolol and atenolol. Xenobiotica 16:435–447
McGourty JC, Silas JH, Lennard MS, Tucker GT, Woods HF (1985) Metoprolol metabolism and debrisoquine oxidation polymorphism—population and family studies. Br J Clin Pharmacol 20:555–566
Nichols AI, Fatato P, Shenouda M, Paul J, Isler JA, Pedersen RD, Jiang Q, Ahmed S, Patroneva A (2009) The effects of desvenlafaxine and paroxetine on the pharmacokinetics of the cytochrome P450 2D6 substrate desipramine in healthy adults. J Clin Pharmacol 49:219–228
Nitti V, 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)
Preskorn SH, Alderman J, Chung M, Harrison W, Messig M, Harris S (1994) Pharmacokinetics of desipramine coadministered with sertraline or fluoxetine. J Clin Psychopharmacol 14:90–98
Sallee FR, Pollock BG (1990) Clinical pharmacokinetics of imipramine and desipramine. Clin Pharmacokinet 18:346–364
Sawamoto T, Lee J, Alak A et al (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 89(Suppl 1):S21
Schmid B, Bircher J, Preisig R, Küpfer A (1985) Polymorphic dextromethorphan metabolism: co-segregation of oxidative O-demethylation with debrisoquin hydroxylation. Clin Pharmacol Ther 38:618–624
Spina E, Pollicino AM, Avenoso A, Campo GM, Perucca E, Caputi AP (1993) Effect of fluvoxamine on the pharmacokinetics of imipramine and desipramine in healthy subjects. Ther Drug Monit 15:243–246
Spina E, Avenoso A, Campo GM, Caputi AP, Perucca E (1995) The effect of carbamazepine on the 2-hydroxylation of desipramine. Psychopharmacology 117:413–416
Spina E, Avenoso A, Campo GM, Caputi AP, Perucca E (1996) Phenobarbital induces the 2-hydroxylation of desipramine. Ther Drug Monit 18:60–64
Steijns LS, Van Der Weide J (1998) Ultrarapid drug metabolism: PCR-based detection of CYP2D6 gene duplication. Clin Chem 44:914–917
Steiner E, Spina E (1987) Differences in the inhibitory effect of cimetidine on desipramine metabolism between rapid and slow debrisoquin hydroxylators. Clin Pharmacol Ther 42:278–282
Stout SM, Nielsen J, Welage LS, Shea M, Brook R, Kerber K, Bleske BE (2011) Influence of metoprolol dosage release formulation on the pharmacokinetic drug interaction with paroxetine. J Clin Pharmacol 51:389–396
Takasu T, Ukai M, Sato S, Matsui T, Nagase I, Maruyama T, Sasamata M, Miyata K, Uchida H, Yamaguchi O (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 321:642–647. doi:10.1124/jpet.106.115840
Takusagawa S, Scheinkoenig J, Buckley D, Miyashita A, Iwatsubo T, Usui T (2012a) In vitro inhibition and induction of human cytochrome P450 enzymes by mirabegron, a potent and selective β3-adrenoceptor agonist. Xenobiotica 42:1187–1196
Takusagawa S, van Lier JJ, Suzuki K, Nagata M, Meijer J, Krauwinkel W, Schaddelee M, Sekiguchi M, Miyashita A, Iwatsubo T, van Gelderen M, Usui T (2012b) Absorption, metabolism and excretion of [(14)C]mirabegron (YM178), a potent and selective beta(3)-adrenoceptor agonist, after oral administration to healthy male volunteers. Drug Metab Dispos 40:815–824
Takusagawa S, Yajima K, Miyashita A, Iwatsubo T, Usui T (2012c) Identification of human CYP isoforms and esterases involved in the metabolism of mirabegron (YM178), a novel selective β3-adrenoceptor agonist. Xenobiotica 42(10):957–967
US Food and Drug Administration (2012) Draft guidance for industry on drug interaction studies—study design, data analysis, implications for dosing and labeling recommendations. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf. Accessed 28 January 2013
van Gelderen E, Li Q, Meijer J, Schaddelee MP, Takusagawa S, Sugawara T, de Koning P (2009) An exploratory comparison of the single dose pharmacokinetics of the β3-adrenoceptor agonist mirabegron in healthy CYP2D6 poor and extensive metabolizers. Clin Pharmacol Ther 85(Suppl 1):S88
Wieling J, Tamminga WJ, Sakiman EP, Oosterhuis B, Wemer J, Jonkman JH (2000) Evaluation of analytical and clinical performance of a dual-probe phenotyping method for CYP2D6 polymorphism and CYP3A4 activity screening. Ther Drug Monit 22:486–496
Yuen KH, Wong JW, Yap SP, Billa N (2001) Estimated coefficient of variation values for sample size planning in bioequivalence studies. Int J Clin Pharmacol Ther 39:37–40
Acknowledgments
The authors wish to thank Sandra Boom (Pharma-Plus) for her assistance in the preparation of this manuscript, funded by Astellas Pharma Europe.
Conflict of interest
Walter Krauwinkel, James Dickinson, Marloes Schaddelee, John Meijer, Reiner Tretter, and Marcel van Gelderen are employees of Astellas Pharma Europe BV. Dr. van de Wetering and Dr. Strabach have no disclosures to declare.
Author information
Authors and Affiliations
Corresponding author
Additional information
Part of this research has been presented at the Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics in 2010.
Rights and permissions
About this article
Cite this article
Krauwinkel, W., Dickinson, J., Schaddelee, M. et al. The effect of mirabegron, a potent and selective β3-adrenoceptor agonist, on the pharmacokinetics of CYP2D6 substrates desipramine and metoprolol. Eur J Drug Metab Pharmacokinet 39, 43–52 (2014). https://doi.org/10.1007/s13318-013-0133-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13318-013-0133-1