The effect of mirabegron, a potent and selective β3-adrenoceptor agonist, on the pharmacokinetics of CYP2D6 substrates desipramine and metoprolol

  • Walter Krauwinkel
  • James Dickinson
  • Marloes Schaddelee
  • John Meijer
  • Reiner Tretter
  • Jeroen van de Wetering
  • Gregory Strabach
  • Marcel van Gelderen
Original Paper


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 (Cmax) 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 Cmax and AUC to last measurable concentration decreased 2.6-fold and 2.2-fold, respectively. In study 2, mirabegron 100 mg/day increased desipramine Cmax 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. Cmax of 2-hydroxydesipramine decreased ~twofold, while AUC increased ~1.3-fold. Desipramine was administered again 2 weeks after the last mirabegron dose. Desipramine Cmax 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).


Mirabegron Metoprolol Desipramine CYP2D6 β3-adrenoceptor Overactive bladder 


  1. 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 78:664–674PubMedCrossRefGoogle Scholar
  2. 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 17:284–291PubMedCrossRefGoogle Scholar
  3. 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 50:838–850PubMedCrossRefGoogle Scholar
  4. European Medicines Agency (2010) Draft Guideline on the Investigation of Drug Interactions. Accessed 28 January 2013
  5. 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 4:271–274PubMedCrossRefGoogle Scholar
  6. 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 70:523–536PubMedCentralPubMedCrossRefGoogle Scholar
  7. 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 67:466–477PubMedCrossRefGoogle Scholar
  8. Harris RZ, Salfi M, Posvar E, Hoelscher D, Padhi D (2007) Pharmacokinetics of desipramine HCl when administered with cinacalcet HCl. Eur J Clin Pharmacol 63:159–163PubMedCrossRefGoogle Scholar
  9. Heim M, Meyer UA (1990) Genotyping of poor metabolisers of debrisoquine by allele-specific PCR amplification. Lancet 336:529–532PubMedCrossRefGoogle Scholar
  10. Hemeryck A, Lefebvre RA, De Vriendt C, Belpaire FM (2000) Paroxetine affects metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers. Clin Pharmacol Ther 67:283–291PubMedCrossRefGoogle Scholar
  11. Johansson I, Lundqvist E, Dahl ML, Ingelman-Sundberg M (1996) PCR-based genotyping for duplicated and deleted CYP2D6 genes. Pharmacogenetics 6:351–355PubMedCrossRefGoogle Scholar
  12. 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 PubMedCrossRefGoogle Scholar
  13. 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 59:893–898PubMedCrossRefGoogle Scholar
  14. 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)Google Scholar
  15. Lennard MS, Tucker GT, Silas JH, Woods HF (1986) Debrisoquine polymorphism and the metabolism and action of metoprolol, timolol, propranolol and atenolol. Xenobiotica 16:435–447PubMedCrossRefGoogle Scholar
  16. 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 20:555–566PubMedCentralPubMedCrossRefGoogle Scholar
  17. 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 49:219–228PubMedCrossRefGoogle Scholar
  18. 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)
  19. Preskorn SH, Alderman J, Chung M, Harrison W, Messig M, Harris S (1994) Pharmacokinetics of desipramine coadministered with sertraline or fluoxetine. J Clin Psychopharmacol 14:90–98PubMedGoogle Scholar
  20. Sallee FR, Pollock BG (1990) Clinical pharmacokinetics of imipramine and desipramine. Clin Pharmacokinet 18:346–364PubMedCrossRefGoogle Scholar
  21. 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):S21Google Scholar
  22. Schmid B, Bircher J, Preisig R, Küpfer A (1985) Polymorphic dextromethorphan metabolism: co-segregation of oxidative O-demethylation with debrisoquin hydroxylation. Clin Pharmacol Ther 38:618–624PubMedCrossRefGoogle Scholar
  23. 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 15:243–246PubMedCrossRefGoogle Scholar
  24. Spina E, Avenoso A, Campo GM, Caputi AP, Perucca E (1995) The effect of carbamazepine on the 2-hydroxylation of desipramine. Psychopharmacology 117:413–416PubMedCrossRefGoogle Scholar
  25. Spina E, Avenoso A, Campo GM, Caputi AP, Perucca E (1996) Phenobarbital induces the 2-hydroxylation of desipramine. Ther Drug Monit 18:60–64PubMedCrossRefGoogle Scholar
  26. Steijns LS, Van Der Weide J (1998) Ultrarapid drug metabolism: PCR-based detection of CYP2D6 gene duplication. Clin Chem 44:914–917PubMedGoogle Scholar
  27. Steiner E, Spina E (1987) Differences in the inhibitory effect of cimetidine on desipramine metabolism between rapid and slow debrisoquin hydroxylators. Clin Pharmacol Ther 42:278–282PubMedCrossRefGoogle Scholar
  28. 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 51:389–396PubMedCentralPubMedCrossRefGoogle Scholar
  29. 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 PubMedCrossRefGoogle Scholar
  30. 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 42:1187–1196PubMedCrossRefGoogle Scholar
  31. 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 40:815–824PubMedCrossRefGoogle Scholar
  32. 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):957–967Google Scholar
  33. US Food and Drug Administration (2012) Draft guidance for industry on drug interaction studies—study design, data analysis, implications for dosing and labeling recommendations. Accessed 28 January 2013
  34. 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):S88Google Scholar
  35. 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 22:486–496PubMedCrossRefGoogle Scholar
  36. 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 39:37–40PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag France 2013

Authors and Affiliations

  • Walter Krauwinkel
    • 1
  • James Dickinson
    • 1
  • Marloes Schaddelee
    • 1
  • John Meijer
    • 2
  • Reiner Tretter
    • 3
  • Jeroen van de Wetering
    • 4
  • Gregory Strabach
    • 5
  • Marcel van Gelderen
    • 1
  1. 1.Global Clinical Pharmacology and Exploratory Development Astellas Pharma Europe BVR.PharmLeidenThe Netherlands
  2. 2.Drug Discovery Research/Drug Metabolism Research Laboratories/Bioanalysis EuropeAstellas Pharma Europe BVLeidenThe Netherlands
  3. 3.Global Data ScienceAstellas Pharma Europe BVLeidenThe Netherlands
  4. 4.Clinical Pharmacology CenterPRA InternationalZuidlarenThe Netherlands
  5. 5.SGS-AsterParisFrance

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