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

BackgroundMirabegron 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.ObjectiveThe 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.MethodsTwo 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.ResultsForty 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 (Cmax) were reached at approximately 2.8–4.0 h postdose. Plasma exposure (Cmax 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.ConclusionsMirabegron 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.

Pharmacokinetics of Mirabegron, a β3-Adrenoceptor Agonist for Treatment of Overactive Bladder, in Healthy East Asian Subjects

“…In a previous report of Japanese singleand multiple-dose studies, the differences in mirabegron exposure were smaller when values were normalized for weight between Japanese and Western subjects. 6 These findings are in accordance with previously published pharmacokinetic profiles in healthy Western subjects. 5,6,8 The effects of food and sex on bioavailability of mirabegron were not clinically relevant.…”

“…These findings are in accordance with previously published single-and multiple-dose studies in healthy Japanese male subjects. 6 Although the 25 and 50 mg dose studies were separately conducted, mirabegron C max and AUC 0-1 increased more than proportionally with dose in Chinese subjects. In addition, after administration of mirabegron in Japanese, Taiwanese, and Chinese subjects, mean values for C max and AUC in female subjects were higher than those in male subjects (Table VI).…”

“…In study 2, urine samples for measurement of unchanged mirabegron were collected no more than 12 hours before dosing and from 0 to 12 hours, 12 to 24 hours, 24 to 48 hours, 48 to 72 hours, and 72 to 96 hours after dosing. In studies 4 and 5, blood samples were collected before dosing and at 0.5, 1, 2, 3, 4, 5, 6,7,8,12,16,24,36,48,72, and 96 hours after dosing in the single-dose period and on the final day in the multiple-dose period, before the first administration of study drug in the multiple-dose period, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, and 24 hours after dosing on the first day in the multiple-dose period, and before dosing on days 5, 6, and 7 in the multiple-dose period. Plasma was collected by centrifugation, and plasma and urine samples were stored at -651C or below until analysis.…”

“…8 In addition, weight is an important consideration when comparing different ethnic populations because weight affects mirabegron pharmacokinetic parameters. 5,6 We conducted 3 food effect studies using single doses of 50 mg in Japanese male subjects (study 1), 50 and 100 mg mirabegron in healthy Japanese male and female subjects (study 2), and 50 mg mirabegron in healthy Taiwanese male and female subjects (study 3). In addition, we conducted 2 studies using single doses of 25 mg mirabegron (study 4) or 50 mg mirabegron (study 5) in healthy Chinese male and female subjects to evaluate the pharmacokinetic parameters, safety profile, and tolerability of mirabegron after single and multiple oral doses.…”

Mirabegron causes relaxation of human and rat corpus cavernosum: could it be a potential therapy for erectile dysfunction?

“…In addition, mirabegron was well tolerated up to the highest doses administered by via oral and i.v. administration [47]. Due to the intrinsic intersubject variability in pharmacokinetic parameters of mirabegron seen in healthy adults, a significant overlap in the plasma exposures of healthy subjects and subjects with hepatic or renal impairment was not a surprising finding [48].…”