title: Role of cytochrome p450 isoenzymes 3A and 2D6 in the in vivo metabolism of mirabegron, a β3-adrenoceptor agonist.
abstract: BACKGROUND
  Mirabegron is a β3-adrenoceptor agonist for the treatment of overactive bladder. There has been little information published or presented about the involvement of cytochrome P450 (CYP) isoenzymes 3A and 2D6 in the metabolism of mirabegron in humans; in vitro data indicate that oxidative metabolism is primarily mediated by CYP3A with a minor role for CYP2D6.
  
  
  OBJECTIVE
  To determine to what extent CYP3A and CYP2D6 isoenzymes are involved in mirabegron metabolism.
  
  
  METHODS
  Two open-label, randomized, one-sequence crossover drug-drug interaction studies in healthy subjects were conducted to assess the effect of ketoconazole and rifampicin on the pharmacokinetics of mirabegron and two parallel-group studies in healthy subjects with either known confirmed or predicted CYP2D6 phenotype.
  
  
  RESULTS
  Co-administration of multiple dosages of 400 mg/day ketoconazole with a single 100 mg mirabegron oral controlled absorption system (OCAS) dose increased mirabegron maximum concentration (C(max)) and area under the curve extrapolated to infinity (AUC∞) to 145 % (90 % confidence interval [CI] 123-172 %] and 181 % (90 % CI 163-201 %), respectively. Co-administration of multiple dosages of 600 mg/day rifampicin with a single 100 mg mirabegron OCAS dose decreased mirabegron C max and AUC∞ to 65 % (90 % CI 50-86 %) and 56 % (90 % CI 49-65 %), respectively, without an effect on terminal elimination half-life (t(½)). The urinary excretion of mirabegron was increased by ketoconazole and decreased by rifampicin, reflecting the AUC changes, whereas renal clearance was not affected. Ketoconazole decreased mirabegron t ½ from 50.9 to 37.6 h suggesting that volume of distribution as well as first-pass effect decreased. Rifampicin did not affect mirabegron t ½, suggesting that it affects first pass through the intestinal wall or liver. Rifampicin greatly increased the ratio to parent drug of the presumed CYP-mediated mirabegron metabolites M8 and M15 by 777 and 646 %. Steady-state mirabegron pharmacokinetic parameters (50 and 100 mg mirabegron OCAS) were similar in 13 CYP2D6 poor, 40 intermediate, and 99 extensive metabolizers, whereas C max and AUC under the dosing interval τ of 24 h (AUCτ) were 30-47 % lower in 10 ultrarapid metabolizers. After administration of 160 mg mirabegron immediate release, C(max) was 14 % and AUC∞ 19 % higher in eight poor metabolizers than in eight extensive metabolizers (phenotyped) with similar t ½. All treatments were well tolerated.
  
  
  CONCLUSIONS
  Mirabegron is metabolized by CYP3A and to a minor extent by CYP2D6 in humans. Mirabegron is not considered a sensitive substrate of CYP3A in vivo, as ketoconazole increased mirabegron exposure by less than 2-fold. The effect of CYP2D6 phenotype on mirabegron exposure is small and likely of limited clinical importance.
authors.affiliation: Astellas Pharma Global Development, Inc, 1 Astellas Way, N2-296, Northbrook, IL 60062, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lee
authors.forename: Selina
authors.initials: S
authors.lastname: Moy
authors.forename: John
authors.initials: J
authors.lastname: Meijer
authors.forename: Walter
authors.initials: W
authors.lastname: Krauwinkel
authors.forename: Taiji
authors.initials: T
authors.lastname: Sawamoto
authors.forename: Virginie
authors.initials: V
authors.lastname: Kerbusch
authors.forename: Donna
authors.initials: D
authors.lastname: Kowalski
authors.forename: Michael
authors.initials: M
authors.lastname: Roy
authors.forename: Alan
authors.initials: A
authors.lastname: Marion
authors.forename: Shin
authors.initials: S
authors.lastname: Takusagawa
authors.forename: Marcel
authors.initials: M
authors.lastname: van Gelderen
authors.forename: James
authors.initials: J
authors.lastname: Keirns
mesh_terms: D000083:Acetanilides / Q000493:pharmacokinetics*; D000293:Adolescent; D058667:Adrenergic beta-3 Receptor Agonists / Q000493:pharmacokinetics*; D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D012293:Rifampin / Q000494:pharmacology; D013844:Thiazoles / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000083:Acetanilides; D058667:Adrenergic beta-3 Receptor Agonists; D013844:Thiazoles; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C520025:mirabegron; D007654:Ketoconazole; D012293:Rifampin