title: Single dose pharmacokinetics and absolute bioavailability of mirabegron, a β₃-adrenoceptor agonist for treatment of overactive bladder.
abstract: OBJECTIVE
  Mirabegron is a potent and selective β3-adrenoceptor agonist in development for treatment of overactive bladder.
  
  
  METHODS
  Mirabegron pharmacokinetics after single intravenous (i.v.) and oral doses, absolute bioavailability (F), dose proportionality, sex differences and tolerability were assessed in 2 single-dose, open-label, randomized, parallel-group, cross-over studies in healthy men (exploratory Study 1, n = 12) and men and women (Study 2, n = 91).
  
  
  RESULTS
  After oral dosing (25 - 150 mg), peak plasma concentrations were attained after ~ 4 h. Mean half-life was around 40 h for both routes of administration. Volume of distribution at steady state was 1,670 l and total clearance was around 57 l/h for i.v. dosing. Mirabegron pharmacokinetics were linear after i.v. dosing (7.5 - 50 mg), but exposure increased more than proportionally after oral dosing due to increased F (29% for 25 mg to 45% at 150 mg). About 20% of the (absorbed) dose was excreted unchanged into urine. Area under the curve (AUC) was 27% and 64% higher in females than males after i.v. and oral dosing respectively; differences were mostly attributed to body weight, and for oral dosing, also to F.
  
  
  CONCLUSIONS
  Mirabegron pharmacokinetics were linear after i.v. dosing (7.5 - 50 mg), but increased more than proportionally after oral dosing (25 - 150 mg) as a result of increased F. Sex differences in exposure could be explained by body weight and for oral dosing, also by F. Mirabegron was in general well tolerated up to the highest doses studied, 50 mg i.v. and 150 mg oral.
authors.affiliation: Astellas Pharma Europe BV, Leiderdorp, The Netherlands.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Eltink
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lee
authors.forename: Marloes
authors.initials: M
authors.lastname: Schaddelee
authors.forename: Wenhui
authors.initials: W
authors.lastname: Zhang
authors.forename: Virginie
authors.initials: V
authors.lastname: Kerbusch
authors.forename: John
authors.initials: J
authors.lastname: Meijer
authors.forename: Sjoerd
authors.initials: S
authors.lastname: van Marle
authors.forename: Nicole
authors.initials: N
authors.lastname: Grunenberg
authors.forename: Donna
authors.initials: D
authors.lastname: Kowalski
authors.forename: Ted
authors.initials: T
authors.lastname: Drogendijk
authors.forename: Selina
authors.initials: S
authors.lastname: Moy
authors.forename: Hiromi
authors.initials: H
authors.lastname: Iitsuka
authors.forename: Marcel
authors.initials: M
authors.lastname: van Gelderen
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsushima
authors.forename: Taiji
authors.initials: T
authors.lastname: Sawamoto
mesh_terms: D000083:Acetanilides / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000293:Adolescent; D058667:Adrenergic beta-3 Receptor Agonists / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D001711:Biotransformation; D001835:Body Weight; D018592:Cross-Over Studies; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D016014:Linear Models; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D009426:Netherlands; D012737:Sex Factors; D013844:Thiazoles / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D053201:Urinary Bladder, Overactive / Q000188:drug therapy*; D014861:Washington; D055815:Young Adult
chemical_list: D000083:Acetanilides; D058667:Adrenergic beta-3 Receptor Agonists; D013844:Thiazoles; C520025:mirabegron