title: Pharmacokinetics of mirabegron, a β3-adrenoceptor agonist for treatment of overactive bladder, in healthy Japanese male subjects: results from single- and multiple-dose studies.
abstract: BACKGROUND
  Mirabegron is a human β3-adrenoceptor agonist for the treatment of overactive bladder. The pharmacokinetic profile of mirabegron has been extensively characterized in healthy Caucasian subjects.
  
  
  OBJECTIVE
  The objective of this study was to evaluate the pharmacokinetics, dose-proportionality, and tolerability of mirabegron following single and multiple oral doses in healthy Japanese male subjects. The results were compared with those reported in non-Japanese (primarily Caucasian) subjects.
  
  
  METHODS
  Two studies were conducted. In a single-blind, randomized, placebo-controlled, parallel-group, single- and multiple-ascending dose study (Study 1), mirabegron oral controlled absorption system (OCAS) tablets were administered at single doses of 50, 100, 200, 300, and 400 mg, with eight subjects (six active, two placebo) per dose group (Part I), and once daily for 7 days at 100 and 200 mg with 12 subjects (eight active, four placebo) per group (Part II). In an open-label, three-period, single-ascending dose study (Study 2), mirabegron OCAS was administered to 12 subjects at 25, 50, and 100 mg in an intra-subject dose-escalation design. Plasma and/or urine samples were collected up to 72 h after the first and last dose and analyzed for mirabegron. Pharmacokinetic parameters were determined using non-compartmental methods. Tolerability assessments included physical examinations, vital signs, 12-lead electrocardiogram, clinical laboratory tests (biochemistry, hematology, and urinalysis), and adverse event (AE) monitoring.
  
  
  RESULTS
  Forty and 24 young male subjects completed Part I and II, respectively, of Study 1. Twelve young males completed Study 2. After single oral doses (25-400 mg), maximum plasma concentrations (C max) were reached at approximately 2.8-4.0 h postdose. Plasma exposure (C max and area under the plasma concentration-time curve) of mirabegron increased more than dose proportionally at single doses of 25-100 mg and approximately dose proportionally at high doses of 300 and 400 mg. A more than dose proportional increase in plasma exposure was noted in the body of the same individual. Mirabegron accumulated twofold upon once-daily dosing relative to single-dose data. Steady state was reached within 7 days. Mirabegron was generally well-tolerated at single doses up to 400 mg and multiple doses up to 200 mg. The AE with the highest incidence was increased pulse rate at 400 mg in Study 1.
  
  
  CONCLUSIONS
  Mirabegron OCAS exhibits similar single- and multiple-dose pharmacokinetic characteristics and deviations from dose proportionality in healthy Japanese male subjects compared with those observed in non-Japanese (primarily Caucasian) subjects in previous studies.
authors.affiliation: Global Project Management, Astellas Pharma Inc., 3-17-1, Hasune, Itabashi-ku, Tokyo, 174-8612, Japan, hiromi.iitsuka@astellas.com.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Iitsuka
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Tokuno
authors.forename: Yoko
authors.initials: Y
authors.lastname: Amada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsushima
authors.forename: Masataka
authors.initials: M
authors.lastname: Katashima
authors.forename: Taiji
authors.initials: T
authors.lastname: Sawamoto
authors.forename: Shin
authors.initials: S
authors.lastname: Takusagawa
authors.forename: Marcel
authors.initials: M
authors.lastname: van Gelderen
authors.forename: Takanori
authors.initials: T
authors.lastname: Tanaka
authors.forename: Hideo
authors.initials: H
authors.lastname: Miyahara
mesh_terms: D000083:Acetanilides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D000322:Adrenergic Agonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D000328:Adult; D044466:Asian People; D004305:Dose-Response Relationship, Drug; D064368:Healthy Volunteers; D006801:Humans; D007564:Japan; D008297:Male; D016037:Single-Blind Method; D013844:Thiazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D053201:Urinary Bladder, Overactive / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000083:Acetanilides; D000322:Adrenergic Agonists; D013844:Thiazoles; C520025:mirabegron