title: Effect of renal or hepatic impairment on the pharmacokinetics of mirabegron.
abstract: OBJECTIVE
  Mirabegron, a selective β3-adrenoceptor agonist for the treatment of overactive bladder (OAB), is eliminated by renal and metabolic routes. The potential influence of renal or hepatic impairment on the pharmacokinetics of mirabegron was evaluated.
  
  
  METHODS
  Two separate open-label, single-dose, parallel-group studies were conducted. Male and female subjects (n = 8 per group) were categorized according to their baseline renal function (mild, moderate, severe or no impairment as determined by estimated glomerular filtration rate [eGFR] using the abbreviated modification of diet in renal disease formula) or hepatic function (mild, moderate or no impairment as determined by the Child-Pugh classification). All subjects received a single oral 100 mg dose of mirabegron. Non-compartmental pharmacokinetic parameters were determined from plasma and urine concentration-time data of mirabegron and metabolites.
  
  
  RESULTS
  Compared with healthy subjects who were similar overall in terms of age, sex and body mass index (BMI), the geometric mean area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC(∞)) for mirabegron was 31, 66 and 118 % higher in subjects with mild, moderate and severe renal impairment, respectively. Peak plasma concentrations (C(max)) increased 6, 23 and 92 %, respectively, in subjects with mild, moderate and severe renal impairment. Renal clearance but not apparent total body clearance of mirabegron correlated well with renal function. Compared with healthy subjects matched for age, sex and BMI, mirabegron AUC(∞) values were 19 and 65 % higher in subjects with mild and moderate hepatic impairment, respectively. Mirabegron C(max) was 9 and 175 % higher, respectively, compared with matched healthy subjects. No clear relationship was evident between pharmacokinetic parameters and Child-Pugh scores. Protein binding was approximately 71 % in healthy subjects and was not altered to a clinically significant extent in subjects with renal or hepatic impairment. No consistent changes in mirabegron elimination half-life were observed in subjects with renal or hepatic impairment. There was high pharmacokinetic variability and significant overlap in exposures between subjects with renal or hepatic impairment and healthy subjects.
  
  
  CONCLUSIONS
  Mirabegron AUC(∞) and C(max) increased 118 and 92 %, respectively, in subjects with severe renal impairment, and 65 and 175 %, respectively, in subjects with moderate hepatic impairment. Pharmacokinetic changes observed in subjects with mild or moderate renal impairment or mild hepatic impairment are of small magnitude and likely to be without clinical importance.
authors.affiliation: Astellas Pharma Europe, Global Clinical Pharmacology Exploratory Development, PO Box 108, 2350 AC, Leiderdorp, The Netherlands.
authors.forename: James
authors.initials: J
authors.lastname: Dickinson
authors.forename: Michaelene
authors.initials: M
authors.lastname: Lewand
authors.forename: Taiji
authors.initials: T
authors.lastname: Sawamoto
authors.forename: Walter
authors.initials: W
authors.lastname: Krauwinkel
authors.forename: Marloes
authors.initials: M
authors.lastname: Schaddelee
authors.forename: James
authors.initials: J
authors.lastname: Keirns
authors.forename: Virginie
authors.initials: V
authors.lastname: Kerbusch
authors.forename: Selina
authors.initials: S
authors.lastname: Moy
authors.forename: John
authors.initials: J
authors.lastname: Meijer
authors.forename: Donna
authors.initials: D
authors.lastname: Kowalski
authors.forename: Richard
authors.initials: R
authors.lastname: Morton
authors.forename: Kenneth
authors.initials: K
authors.lastname: Lasseter
authors.forename: Dennis
authors.initials: D
authors.lastname: Riff
authors.forename: Viera
authors.initials: V
authors.lastname: Kupčová
authors.forename: Marcel
authors.initials: M
authors.lastname: van Gelderen
mesh_terms: D000083:Acetanilides / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000284:Administration, Oral; D058667:Adrenergic beta-3 Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D005260:Female; D005919:Glomerular Filtration Rate; D006207:Half-Life; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000503:physiopathology; D007674:Kidney Diseases / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology; D008099:Liver / Q000378:metabolism* / Q000503:physiopathology; D008107:Liver Diseases / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D012720:Severity of Illness Index; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
chemical_list: D000083:Acetanilides; D058667:Adrenergic beta-3 Receptor Agonists; D013844:Thiazoles; C520025:mirabegron