BACKGROUND Mirabegron (YM178) is a β(3)-adrenoceptor agonist for the treatment of overactive bladder (OAB). As part of the clinical development program for mirabegron, 2 human volunteer studies were performed to derive detailed data on the multiple-dose pharmacokinetic (PK) properties of mirabegron. OBJECTIVE Two randomized Phase I studies were conducted to evaluate the PK properties of mirabegron, including metabolic profile and effects of age and sex, following multiple oral doses in healthy subjects. METHODS In study 1, mirabegron oral controlled absorption system (OCAS) tablets were administered once daily to healthy young subjects (18-55 years) at doses of 50, 100, 200, and 300 mg and in elderly subjects (65-80 years) at 50 and 200 mg in a double-blind placebo-controlled, parallel-group design. In study 2, mirabegron OCAS was administered once daily to healthy young (18-45 years) and older (≥55 years) subjects at doses of 25, 50, and 100 mg in an open-label crossover design. Blood samples were collected up to 72 hours (study 1) and 168 hours (study 2) after the last dose. Urine samples were collected up to 24 hours after the last dose. Plasma and urine concentrations of mirabegron and its metabolites (study 2 only) were analyzed by LC-MS/MS. PK parameters were determined using noncompartmental methods. Tolerability assessments included physical examinations, supine blood pressure and pulse rate, orthostatic stress testing (study 1), resting 12-lead ECGs, clinical laboratory tests (biochemistry, hematology, and urinalysis), and adverse-events (AE) monitoring using investigators' questionnaires and subjects' spontaneous reports. RESULTS Thirty-two young male (mean age, 30.3 years; mean weight, 77.1 kg), 32 young female (27.6 years; 64.6 kg), 16 elderly male (69.8 years; 79.3 kg), and 16 elderly female (68.1 years; 67.4 kg) subjects were enrolled in study 1. Eighteen young male (mean age, 28.6 years; mean weight, 68.9 kg), 18 young female (28.7 years; 58.8 kg), 21 older male (63.4 years; 72.6 kg), and 18 older female (65.1 years; 62.3 kg) subjects were enrolled in study 2. Most of the subjects were white (91% in study 1 and 88% in study 2). Mirabegron plasma concentrations peaked at ∼3 to 5 hours and declined multiexponentially with a t of ∼32 hours in study 1 and 60 hours in study 2. Steady state was achieved within 7 days of once daily administration, with an accumulation ratio of ∼2. Mirabegron and its metabolites demonstrated a greater-than-dose-proportional increase in C(max) and AUC(0-τ) after multiple-dose administration. Two major circulating metabolites were observed, representing 17% and 10% of total drug-related AUC(0-τ). Excretion of unchanged mirabegron in urine over the 24-hour dosing interval (Ae(0-τ)%) increased from approximately 7% at 25 mg to 18% at 300 mg once daily in young subjects. Renal clearance (CL(R)) of mirabegron was independent of dose and averaged ∼13 L/h. Mirabegron C(max) and AUC(0-τ) were similar in older and young subjects. Women exhibited ∼40% higher mirabegron C(max) and AUC(0-τ) than men; weight-corrected values were ∼20% higher in women. Mirabegron was generally well tolerated up to 300 mg once daily. No clear trends for increased incidence of AEs occurred with higher doses of mirabegron. The AE with the highest incidence was headache. CONCLUSION Oral mirabegron exhibited a greater-than-dose-proportional increase in exposure. Sex but not age significantly affected mirabegron exposure. ClinicalTrials.gov identifier: NCT01478503 (Study 1) and NCT01285596 (Study 2).