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

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).

• Authors: Walter Krauwinkel, James Dickinson, Marloes Schaddelee, John Meijer, Reiner Tretter, Jeroen van de Wetering, Gregory Strabach, Marcel van Gelderen
• Journal: European journal of drug metabolism and pharmacokinetics (Eur J Drug Metab Pharmacokinet) Vol. 39 Issue 1 Pg. 43-52 (Mar 2014) ISSN: 0378-7966 [Print] France
• PMID: 23728524 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acetanilides
• Adrenergic beta-3 Receptor Agonists
• Cytochrome P-450 CYP2D6 Inhibitors
• Enzyme Inhibitors
• Thiazoles
• Cytochrome P-450 CYP2D6
• Metoprolol
• mirabegron
• Desipramine

Topics

• Acetanilides (administration & dosage, adverse effects)
• Adolescent
• Adrenergic beta-3 Receptor Agonists (administration & dosage, adverse effects)
• Adult
• Area Under Curve
• Cross-Over Studies
• Cytochrome P-450 CYP2D6 (genetics, metabolism)
• Cytochrome P-450 CYP2D6 Inhibitors
• Desipramine (administration & dosage, adverse effects, blood, pharmacokinetics)
• Drug Interactions
• Enzyme Inhibitors (administration & dosage)
• Female
• Half-Life
• Healthy Volunteers
• Humans
• Male
• Metabolic Clearance Rate
• Metoprolol (administration & dosage, adverse effects, blood, pharmacokinetics)
• Middle Aged
• Thiazoles (administration & dosage, adverse effects)
• Urinary Bladder, Overactive (drug therapy)
• Young Adult