European Journal of Drug Metabolism and Pharmacokinetics

, Volume 39, Issue 1, pp 43–52

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

Authors

    • Global Clinical Pharmacology and Exploratory Development Astellas Pharma Europe BVR.Pharm
  • James Dickinson
    • Global Clinical Pharmacology and Exploratory Development Astellas Pharma Europe BVR.Pharm
  • Marloes Schaddelee
    • Global Clinical Pharmacology and Exploratory Development Astellas Pharma Europe BVR.Pharm
  • John Meijer
    • Drug Discovery Research/Drug Metabolism Research Laboratories/Bioanalysis EuropeAstellas Pharma Europe BV
  • Reiner Tretter
    • Global Data ScienceAstellas Pharma Europe BV
  • Jeroen van de Wetering
    • Clinical Pharmacology CenterPRA International
  • Gregory Strabach
    • SGS-Aster
  • Marcel van Gelderen
    • Global Clinical Pharmacology and Exploratory Development Astellas Pharma Europe BVR.Pharm
Original Paper

DOI: 10.1007/s13318-013-0133-1

Cite this article as:
Krauwinkel, W., Dickinson, J., Schaddelee, M. et al. Eur J Drug Metab Pharmacokinet (2014) 39: 43. doi:10.1007/s13318-013-0133-1

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).

Keywords

Mirabegron Metoprolol Desipramine CYP2D6 β3-adrenoceptor Overactive bladder

Copyright information

© Springer-Verlag France 2013