title: Pharmacokinetic Interactions Between Mirabegron and Metformin, Warfarin, Digoxin or Combined Oral Contraceptives.
abstract: OBJECTIVE
  Mirabeg ron is a selective β3-adrenoceptor agonist approved for the treatment of overactive bladder (OAB). Four phase 1 studies were conducted in healthy subjects to evaluate the potential for pharmacokinetic interactions between mirabegron and metformin, warfarin, digoxin, or a combination oral contraceptive (COC).
  
  
  METHODS
  Thirty-two male subjects received metformin (500 mg twice daily) or mirabegron (160 mg once daily) alone, in combination or with placebo. Twenty-four male and female subjects received single doses of warfarin (25 mg) alone and in combination with mirabegron (100 mg once daily). Twenty-five male and female subjects were administered digoxin (0.25 mg) alone and in combination with mirabegron (100 mg once daily). Thirty female subjects received low-dose COC containing ethinylestradiol (EE)/levonorgestrel (LNG) (30/150 µg once daily) in combination with mirabegron (100 mg once daily) or placebo. Pharmacokinetic parameters were determined by non-compartmental methods. Absence of a Pharmacokinetic interaction was concluded if the 90 % confidence intervals (CI) of geometric least-squares means ratio of area under the curve (AUC) and maximum concentration (Cmax) were contained within the standard 80-125 % no-effect boundaries. The effect of mirabegron on warfarin International Normalized Ratio (INR) was also assessed.
  
  
  RESULTS
  Mirabegron increased digoxin AUC and Cmaxby 27 and 29 %, respectively, indicating that mirabegron is a weak inhibitor of P-glycoprotein (P-gp) in vivo. Co-administration of mirabegron did not affect the pharmacokinetics of metformin, warfarin, EE and LNG, or warfarin INR, except for a slight extension of the 90 % CI for the Cmaxratio for metformin (lower limit 79 %). Metformin decreased mirabegron AUC and Cmaxby 21 %. Most treatment-emergent adverse events were mild, and all resolved by study end.
  
  
  CONCLUSIONS
  No dose adjustment of either drug is required when mirabegron is administered concomitantly with metformin, warfarin or COC. Patients receiving mirabegron with digoxin may require additional monitoring of digoxin concentrations with dose adjustments where necessary, due to its narrow therapeutic index.
authors.affiliation: Astellas Pharma Europe, Clinical Pharmacology Exploratory Development, PK&MS, Sylviusweg 62, PO Box 344, 2300 BE, Leiden, The Netherlands.
authors.forename: Monique
authors.initials: M
authors.lastname: Groen-Wijnberg
authors.affiliation: Astellas Pharma Europe, Clinical Pharmacology Exploratory Development, PK&MS, Sylviusweg 62, PO Box 344, 2300 BE, Leiden, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: van Dijk
authors.affiliation: Astellas Pharma Europe, Clinical Pharmacology Exploratory Development, PK&MS, Sylviusweg 62, PO Box 344, 2300 BE, Leiden, The Netherlands. walter.krauwinkel@astellas.com.
authors.forename: Walter
authors.initials: W
authors.lastname: Krauwinkel
authors.affiliation: PharmAspire Consulting, De Meren 1203, 6605 XM, Wijchen, The Netherlands.
authors.forename: Virginie
authors.initials: V
authors.lastname: Kerbusch
authors.affiliation: Astellas Pharma Europe, Clinical Pharmacology Exploratory Development, PK&MS, Sylviusweg 62, PO Box 344, 2300 BE, Leiden, The Netherlands.
authors.forename: John
authors.initials: J
authors.lastname: Meijer
authors.affiliation: Astellas Pharma Europe, Clinical Pharmacology Exploratory Development, PK&MS, Sylviusweg 62, PO Box 344, 2300 BE, Leiden, The Netherlands.
authors.forename: Reiner
authors.initials: R
authors.lastname: Tretter
authors.affiliation: Astellas Pharma, One Astellas Way, Northbrook, IL, 60062, USA.
authors.forename: Wenhui
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Astellas Pharma Europe, Clinical Pharmacology Exploratory Development, PK&MS, Sylviusweg 62, PO Box 344, 2300 BE, Leiden, The Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: van Gelderen
mesh_terms: D000083:Acetanilides / Q000493:pharmacokinetics* / Q000627:therapeutic use; D058667:Adrenergic beta-3 Receptor Agonists / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000328:Adult; D019540:Area Under Curve; D003277:Contraceptives, Oral, Combined / Q000493:pharmacokinetics*; D004077:Digoxin / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D004347:Drug Interactions / Q000502:physiology*; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008687:Metformin / Q000493:pharmacokinetics*; D013844:Thiazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use; D053201:Urinary Bladder, Overactive / Q000188:drug therapy; D014859:Warfarin / Q000493:pharmacokinetics*
chemical_list: D000083:Acetanilides; D058667:Adrenergic beta-3 Receptor Agonists; D003277:Contraceptives, Oral, Combined; D013844:Thiazoles; D014859:Warfarin; D004077:Digoxin; D008687:Metformin; C520025:mirabegron