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

• Published in: European journal of drug metabolism and pharmacokinetics 2014-03, Vol.39 (1), p.43-52
• Main Authors: Krauwinkel, Walter, Dickinson, James, Schaddelee, Marloes, Meijer, John, Tretter, Reiner, van de Wetering, Jeroen, Strabach, Gregory, van Gelderen, Marcel
• Format: Article
• Language: English
• Subjects: Acetanilides - administration & dosage; Acetanilides - adverse effects; Adolescent; Adrenergic beta-3 Receptor Agonists - administration & dosage; Adrenergic beta-3 Receptor Agonists - adverse effects; Adult; Area Under Curve; Biomedical and Life Sciences; Biomedicine; Cross-Over Studies; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P-450 CYP2D6 - metabolism; Cytochrome P-450 CYP2D6 Inhibitors; Desipramine - administration & dosage; Desipramine - adverse effects; Desipramine - blood; Desipramine - pharmacokinetics; Drug Interactions; Enzyme Inhibitors - administration & dosage; Female; Half-Life; Healthy Volunteers; Human Physiology; Humans; Male; Medical Biochemistry; Metabolic Clearance Rate; Metoprolol - administration & dosage; Metoprolol - adverse effects; Metoprolol - blood; Metoprolol - pharmacokinetics; Middle Aged; Original Paper; Pharmaceutical Sciences/Technology; Pharmacology/Toxicology; Pharmacy; Thiazoles - administration & dosage; Thiazoles - adverse effects; Urinary Bladder, Overactive - drug therapy; Young Adult
• ISSN: 0378-7966; 2107-0180
• DOI: 10.1007/s13318-013-0133-1

Mirabegron is a potent and selective β 3 -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 (AUC 0-∞ ) 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 AUC 0-∞ 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 AUC 0-∞ 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