title: Effects of food intake on the pharmacokinetic properties of mirabegron oral controlled-absorption system: a single-dose, randomized, crossover study in healthy adults.
abstract: BACKGROUND
  Mirabegron is a β3-adrenoceptor agonist used for the treatment of overactive bladder. Mirabegron is formulated as an extended-release tablet using oral controlled-absorption system (OCAS) technology.
  
  
  OBJECTIVE
  This study was designed to assess the effects of food on the pharmacokinetic properties of mirabegron OCAS in accordance with regulatory requirements to support dosing recommendations.
  
  
  METHODS
  In this single-dose, randomized, open-label, 3-period, parallel-dose-group, crossover study, mirabegron OCAS 50 or 100 mg was administered orally to healthy adult subjects in the fasted state or after a high- or low-fat breakfast. Dose administrations were separated by a washout period of at least 10 days. Blood samples were drawn up to 96 hours after dosing, and plasma concentrations of mirabegron were analyzed by LC/MS-MS. PK properties were determined using noncompartmental methods. Primary end points for the assessment of food effects were Cmax and AUC0-∞. For tolerability assessment, adverse events (AEs) were monitored using investigators' questionnaires and subjects' spontaneous reports, vital sign measurements, hematology, clinical chemistry, and ECG.
  
  
  RESULTS
  Thirty-eight subjects (male, 50%; mean age, 32.1 years; mean weight, 77.3 kg; race, 76.3% white) were enrolled in the 50-mg dose group and 38 subjects (male, 52.6%; mean age, 30.9 years; mean weight, 74.5 kg; race, 63.2% white) in the 100-mg dose group. With either fed condition or dose, the 90% CIs for the fed/fasted ratios of both Cmax and AUC0-∞ of mirabegron fell below the predetermined range for bioequivalence (80.0%-125.0%), suggesting that food had no effect on exposure to mirabegron OCAS. With the 50-mg dose, mirabegron Cmax was reduced by 45% with a high-fat breakfast compared with fasted conditions (geometric mean ratio [GMR], 54.8% [90% CI, 43.7%-68.6%]) and AUC0-∞, by 17% (GMR, 83.2% [90% CI, 74.2%-93.4%]). With the 100-mg dose, mirabegron Cmax and AUC0-∞ were reduced by 39% (GMR, 61.3% [90% CI, 47.8%-78.7%]) and 18% (82.4% [72.6%-93.5%]), respectively, after a high-fat breakfast. With the 50-mg dose, mirabegron Cmax was decreased by 75% (GMR, 25.0% [90% CI, 19.9%-31.3%]) and AUC0-∞ by 51% (48.7% [43.3%-54.7%]) after a low-fat breakfast. Corresponding reductions with the 100-mg dose were 64% (GMR, 36.3% [90% CI, 28.2%-46.8%]) for Cmax and 47% (GMR, 53.2% [90% CI, 46.8%-60.5%]) for AUC0-∞. The fed/fasted ratios for mirabegron Cmax and AUC0-∞ were in general independent of dose or sex. Food delayed Tmax compared with the fasted state, with similar increases with the high- and low-fat meals (0.9 hours with 50 mg and 1.5-2.0 hours with 100 mg). Mirabegron was generally well tolerated, with no apparent difference in AE frequency between the fasted and fed states.
  
  
  CONCLUSIONS
  Mirabegron OCAS tablets exhibited a decrease in mirabegron plasma exposure with food that was independent of dose (50 or 100 mg) or gender but dependent on meal composition. A greater reduction in mirabegron exposure was observed after a low-fat breakfast compared with after a high-fat breakfast. Based on findings from previous studies, the effects of food observed in this study do not warrant dose adjustment in clinical practice. ClinicalTrials.gov identifier: NCT00939757.
authors.affiliation: Astellas Pharma Global Development Inc, Northbrook, IL 60062, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lee
authors.forename: Wenhui
authors.initials: W
authors.lastname: Zhang
authors.forename: Selina
authors.initials: S
authors.lastname: Moy
authors.forename: Donna
authors.initials: D
authors.lastname: Kowalski
authors.forename: Virginie
authors.initials: V
authors.lastname: Kerbusch
authors.forename: Marcel
authors.initials: M
authors.lastname: van Gelderen
authors.forename: Taiji
authors.initials: T
authors.lastname: Sawamoto
authors.forename: Nicole
authors.initials: N
authors.lastname: Grunenberg
authors.forename: James
authors.initials: J
authors.lastname: Keirns
mesh_terms: D000083:Acetanilides / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000328:Adult; D018592:Cross-Over Studies; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D008297:Male; D012016:Reference Values; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000083:Acetanilides; D000318:Adrenergic beta-Agonists; D013844:Thiazoles; C520025:mirabegron