title: 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.affiliation: Global Clinical Pharmacology and Exploratory Development Astellas Pharma Europe BV, R.Pharm, Sylviusweg 62, PO Box 344, 2300 AH, Leiden, The Netherlands, Walter.Krauwinkel@astellas.com.
authors.forename: Walter
authors.initials: W
authors.lastname: Krauwinkel
authors.forename: James
authors.initials: J
authors.lastname: Dickinson
authors.forename: Marloes
authors.initials: M
authors.lastname: Schaddelee
authors.forename: John
authors.initials: J
authors.lastname: Meijer
authors.forename: Reiner
authors.initials: R
authors.lastname: Tretter
authors.forename: Jeroen
authors.initials: J
authors.lastname: van de Wetering
authors.forename: Gregory
authors.initials: G
authors.lastname: Strabach
authors.forename: Marcel
authors.initials: M
authors.lastname: van Gelderen
mesh_terms: D000083:Acetanilides / Q000008:administration & dosage* / Q000009:adverse effects; D000293:Adolescent; D058667:Adrenergic beta-3 Receptor Agonists / Q000008:administration & dosage* / Q000009:adverse effects; D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003891:Desipramine / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008790:Metoprolol / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D013844:Thiazoles / Q000008:administration & dosage* / Q000009:adverse effects; D053201:Urinary Bladder, Overactive / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000083:Acetanilides; D058667:Adrenergic beta-3 Receptor Agonists; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D013844:Thiazoles; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol; C520025:mirabegron; D003891:Desipramine