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

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 (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).

Keywords

Mirabegron Metoprolol Desipramine CYP2D6 β3-adrenoceptor Overactive bladder 

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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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