Pharmacokinetics of Mirabegron, a β3-Adrenoceptor Agonist for Treatment of Overactive Bladder, in Healthy Japanese Male Subjects: Results from Single- and Multiple-Dose Studies
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- Iitsuka, H., Tokuno, T., Amada, Y. et al. Clin Drug Investig (2014) 34: 27. doi:10.1007/s40261-013-0146-1
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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.
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.
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.
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 (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.
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.
Mirabegron is an agonist of the human β3-adrenoceptor, discovered by Astellas Pharma Inc. in Japan . β3-Adrenoceptors have been shown to play a role in the relaxation of the urinary bladder detrusor smooth muscle . Mirabegron relaxes the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle by activation of β3-adrenoceptor, which increases bladder capacity [1, 3]. Mirabegron has been approved in Japan, the USA, and the EU for the treatment of overactive bladder (OAB) [4, 5] and is the first of a new class of oral compounds with a different mode of action than antimuscarinic medications, the current mainstay treatment for patients with OAB .
The pharmacokinetic profile of mirabegron after single and multiple oral doses has been reported in cohorts of Western, primarily Caucasian, healthy adult subjects [7, 8]. Mirabegron demonstrated a greater than dose-proportional increase in maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) after single and multiple oral doses, which was due to an increase in absolute bioavailability with increasing dose (from 25 % at 25 mg to 40 % at 100 mg) [7, 8]. Mirabegron was cleared by multiple mechanisms (renal and possibly biliary excretion of unchanged drug, and metabolism by multiple enzymes), with no single predominating clearance pathway . In vitro studies suggested a role for the polymorphic cytochrome P450 (CYP) 2D6 enzyme in the oxidative metabolism of mirabegron, in addition to CYP3A , although in vivo results indicated that these isozymes play a limited role in the overall elimination [11, 12]. In addition, body weight is an important consideration when comparing different ethnic populations, as body weight has been shown to affect mirabegron pharmacokinetics .
As part of the clinical development program in Japan, we conducted two studies using single doses of mirabegron 25–400 mg and multiple doses of 100 and 200 mg/day in healthy Japanese male subjects to evaluate the pharmacokinetics, dose-proportionality, and tolerability of mirabegron after single and multiple oral doses. The pharmacokinetic results obtained in Japanese subjects in these studies were subsequently compared with those previously reported for non-Japanese (primarily Caucasian) healthy male subjects.
Both studies were conducted in accordance with the ethical principles based on the Declaration of Helsinki  and Good Clinical Practice , as defined by the Ministerial Ordinance concerning the standards for the implementation of clinical studies on pharmaceutical products, and the regulations stipulated in the Japanese Pharmaceutical Affairs Law. The studies were conducted at two centers and approved by institutional review boards.
Subjects were eligible for inclusion in the studies if they met the following criteria: for Study 1, males aged 20–44 years inclusive, with a body weight of 50.0 to <80.0 kg and a body mass index (BMI) of 18.5 to <25.0 kg/m2; for Study 2, males aged 20–44 years inclusive, with a body weight of 50.0 to <80.0 kg and a BMI of 17.6 to <26.4 kg/m2. Major exclusion criteria for both studies were current or previous hepatic, renal, heart, respiratory, or gastrointestinal disease or cerebrovascular disorder; concurrent or previous malignant tumor; upper gastrointestinal disease within 7 days prior to the start of the study (Study 2 only); any clinically significant deviation from normal in physical examination, vital signs, electrocardiogram (ECG) or clinical laboratory determinations; history of drug allergy; history of hypersensitivity to β-adrenoceptor agonists or exposure to study drug (Study 2 only); prior exposure to long-term medication (at least 28 days; Study 1 only), any investigational drug within 120 days, or prescription or over-the-counter medications within 1 week prior to the start of the study. In both studies, concomitant medication was not allowed throughout the duration of the study. All subjects provided written informed consent before screening.
2.2 Study Designs
Study 1 was a single-blind, randomized, placebo-controlled, parallel group, single- and multiple-dose escalation study in 64 healthy male subjects to assess the single- and multiple dose pharmacokinetics and tolerability of mirabegron, formulated as a sustained release tablet using the oral controlled absorption system (OCAS) technology . The study consisted of two parts. In Part I, each subject received a single oral dose of mirabegron [50, 100, 200, 300 (as 100 + 200 mg tablet), or 400 mg (as 2 × 200 mg tablet)] or matching placebo (n = 6 active, n = 2 placebo) with 200 mL of water. Subjects were fasted overnight prior to dosing and remained fasted until 4 h postdose. In Part II, each subject received a single oral dose of mirabegron (100 or 200 mg) or matching placebo (n = 8 active, n = 4 placebo) with 200 mL of water, followed by a 2-day washout period and once-daily oral doses for 7 days (Days 4–10). Dosing occurred within 30 min to 1 h after breakfast and no additional food was served until 4 h postdose. Subjects were admitted to the clinical site on the day before dosing (Day −1) and were confined until discharge on Day 4 (Part I) or Day 13 (Part II). Subjects underwent a post-study visit 4 days after the last administration or after early discontinuation.
Study 2 was a single-dose, open-label, three-period, intra-subject dose-escalation study in 12 healthy male subjects to assess the dose proportionality of the mirabegron OCAS. Each subject received escalating single doses of mirabegron 25, 50 and 100 (as 2 × 50 mg tablet) mg with 150 mL of water in three separate treatment periods, with a washout period of at least 12 days between treatments. Subjects were fasted overnight prior to dosing and remained fasted until 4 h postdose. Subjects were admitted to the clinical site on the day before dosing (Day −1) and were confined until discharge on Day 4 of each treatment period. Subjects underwent a post-study visit within 13–17 days after the last administration or after early discontinuation.
2.3 Sample Collection and Analysis
In Study 1, blood samples for plasma mirabegron concentrations were collected into tubes containing sodium-EDTA as anticoagulant and sodium fluoride as stabilizer at predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 24, 36, 48, and 72 h postdose in Part I, and at predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 24, 36, 48, and 72 h postdose on Days 1 and 10, and predose on Days 5, 6, 7, 8, and 9 of Part II. In Study 2, blood samples for plasma mirabegron concentrations were collected into tubes containing sodium-heparin as anticoagulant and sodium fluoride as stabilizer at predose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 24, 36, 48, and 72 h postdose in all periods. In Part I and Part II (Days 1 and 10) of Study 1, urine samples for measurement of unchanged mirabegron were collected within 12 h prior to dosing (Part I and Day 1 of Part II) and from 0 to 12, 12 to 24, 24 to 36, 36 to 48, and 48 to 72 h postdose.
Plasma was collected by centrifugation and plasma and urine samples were stored at −65 °C or below and −20 °C or below, respectively, until analysis. Liquid–liquid extraction was used to extract mirabegron from plasma constituents. Urine samples were diluted prior to analysis. Samples were assayed by validated liquid chromatography analytical methods coupled with tandem mass spectrometric detection (LC–MS/MS) using an atmospheric pressure chemical ionization interface, as described previously with minor modifications . The calibration ranges were 1.0–500 ng/mL in plasma and 2.0–1,000 ng/mL in urine for Study 1, and 0.2–100 ng/mL in plasma for Study 2. In the bioanalytical method validation studies, within-run precision of quality control (QC) standards was less than 5.8 % for plasma and less than 7.2 % for urine. The within-run accuracy (relative error) of the assays over the QC range ranged from −5.0 to 10.0 % for plasma and from −6.9 to 13.0 % for urine.
2.4 Pharmacokinetic Analysis
Concentration data of mirabegron in plasma and urine were analyzed by non-compartmental methods using SAS® version 8.2 (SAS Institute, Cary, NC, USA), or WinNonlin Professional® version 5.0.1 (Study 1) or 5.2.1 (Study 2) (CERTARA, St. Louis, MO, USA). The following pharmacokinetic parameters were obtained as applicable and as appropriate for each study : Cmax; time to reach Cmax (tmax); AUC (obtained by the linear-logarithmic trapezoidal method) from time zero to 24 h (AUC24) and AUC from time zero to infinity (AUC∞) after single-dose administration, and AUC during a dosage interval (AUCτ); terminal elimination half-life (t½β); apparent total body clearance from plasma after oral administration (CL/F); apparent volume of distribution during terminal phase after non-intravenous administration (Vz/F); cumulative percentage of unchanged drug excreted into the urine (Ae%) up to 72 h postdose; and renal clearance (CLR). Actual sampling times were used in all calculations involving sampling times, and nominal sampling times were used for the mean concentration–time figures.
2.5 Tolerability Assessments
Tolerability was assessed based on physical examinations, vital signs (axillary body temperature, supine blood pressure, and supine pulse rate), resting 12-lead ECGs, standard clinical laboratory tests (hematology, blood biochemistry, urinalysis), and adverse event (AE) monitoring. Clinically significant adverse changes in any tolerability assessment, including symptoms and signs, vital signs, ECGs, and clinical laboratory tests, were considered AEs. AEs were collected from the time of dosing until the end of the study. The causal relationships for all AEs were categorized by the investigator as probable, possible, or not related.
2.6 Statistical Methods
Tolerability data were evaluated descriptively, and AEs were described in their entirety. All randomized subjects who received at least one dose of study drug were included in the tolerability analyses. Summary statistics were calculated for all pharmacokinetic parameters by dose. All subjects who received at least one dose of study drug and had at least one mirabegron plasma concentration measured were included in the pharmacokinetic analysis.
In both studies, dose-proportionality was examined for natural log transformed Cmax and AUC∞ using a power model . The following model was used: ln(pharmacokinetic parameter) = β0 + β1·ln(dose), where β0 is the intercept and β1 is the slope of the model. Dose proportionality was concluded if the 95 % confidence interval (CI) for β1 included 1 . To assess accumulation of mirabegron with multiple dosing (Study 1), 90 % CIs around the geometric mean ratio (GMR) of mirabegron Cmax and AUCτ on Day 10 versus Cmax and AUC24 on Day 1 were constructed. To evaluate if mirabegron demonstrates linear pharmacokinetics with time during repeated administration, 90 % CIs around the GMR for mirabegron AUCτ on Day 10 versus AUC∞ on Day 1 were constructed. For linear pharmacokinetics with time, the AUCτ at steady state is equal to the AUC∞ following a single dose (i.e., a ratio of 1) . The MIXED procedure of SAS® version 8.2 was used for all statistical analyses, with subjects as a random effect in Study 2.
3.1 Study Population
Subject demographics in the single- and multiple ascending dose study (Study 1)
Single dose (Part I)
Multiple dose (Part II)
Body weight (kg)
3.2 Pharmacokinetics of Mirabegron
3.2.1 Single Dose
Pharmacokinetic parameters of mirabegron after single oral doses of mirabegron oral controlled absorption system under fasting
Study 1 Part I
3.2.2 Multiple Dose
Pharmacokinetic parameters of mirabegron after single and multiple oral doses of mirabegron oral controlled absorption system in Study 1 (Part II)
In Study 1 Part I, 12 AEs were reported by eight (20 %) of the 40 subjects, and nine of these were considered by the investigator to be related to study drug. The AEs were all mild in intensity and occurred in one (17 %), three (50 %), and four (67 %) subjects in the 100, 300, and 400 mg groups, respectively. No AEs were observed in the placebo, 50 or 200 mg groups. The most common AEs (reported by ≥2 subjects) were increased pulse rate and increased blood amylase. Pulse rates exceeding 100 beats/min at 4–6 h after dosing occurred in three of six subjects in the 400 mg group. One of these three subjects with increased heart rate also developed palpitations at 3 h after dosing. There were no episodes of clinically significant increases in pulse rate or palpitations in other dose groups. Pulse rate tended to increase in a dose-dependent manner at 6 h postdose in the 200 mg and higher dose groups compared with the placebo group. Increases in blood amylase that were considered AEs by the investigator, occurred in two of six subjects in the 300 mg group and one of six subjects in the 100 mg group. In Part II, eight AEs were reported by five (21 %) of the 24 subjects, and two of these were considered by the investigator to be related to study drug. The AEs occurred in two (25 %), two (25 %), and one (12.5 %) subjects in the placebo, 100, and 200 mg groups, respectively. All AEs were mild in intensity and reported by one subject each. Increases in pulse rate were observed at 6 h after the first administration in the 200 mg group and at 6 h after the last administration in the 100 and 200 mg groups as compared with the placebo group. None of the pulse rate increases were judged clinically significant by the investigator. There were no clinically significant changes in blood pressure, body temperature, 12-lead ECG, or physical examination results.
In Study 2, there were six AEs reported by four (33 %) of the 12 subjects, and five of these were considered by the investigator to be related to study drug. Of the six AEs, two and four events occurred in two and three subjects receiving a 25 and 50 mg dose, respectively. All were mild in intensity and reported by one subject each. Mean supine pulse rate at 6 h postdose appeared to show a dose-dependent increase. Mean systolic blood pressure tended to increase at 3–6 h postdose; however, it was considered to be due to circadian rhythm. There were no apparent changes in mean diastolic blood pressures and no clinically significant findings in ECG data. No deaths, serious AEs, or AEs requiring symptomatic therapy occurred in either study. All AEs resolved spontaneously.
In these studies in healthy Japanese male subjects, mirabegron Cmax were reached on average within 2.8–4.0 h following single-dose oral administration and at 5.0 h following multiple-dose administration. Steady-state conditions were reached by 7 days of once-daily administration with mirabegron, and accumulation of mirabegron was about twofold. These findings are in accordance with previously published single- and multiple-dose studies in healthy non-Japanese individuals, which mainly comprised Caucasians (60–100 %) [7, 8]. The mean t½β of mirabegron (25.1–36.4 h) was consistent with the range observed in non-Japanese males following single- (27.9–40.6 h) and multiple-dose administration (29.2–36.8 h) in those previous studies that used a similar sampling duration (up to 72 or 96 h postdose) as the present studies [7, 8].
A greater than dose-proportional increase in exposure was observed following single-dose administration across the 25–100 mg dose range, resulting in a predicted 2.8- and 2.5-fold increase in mirabegron Cmax and AUC∞, respectively, with each doubling of the dose within this dose range. Similar deviations from dose proportionality (approximately 3.0-fold for Cmax and 2.7-fold for AUC∞) were observed in a single-dose pharmacokinetics study in healthy non-Japanese male subjects using the same dose range . Above 100 mg, the dose non-proportionality was much less marked as the normalized AUC–dose relationship began to reach a maximum. A postulated mechanism for the non-proportionality of mirabegron pharmacokinetics after oral administration is the decrease in the action of gut efflux transporters (predominantly P-glycoprotein) with increasing doses that reduce the bioavailability of mirabegron . The efflux ability of these transporters may be saturated at higher doses (above 100 mg), resulting in a return to dose proportionality.
A small increase (28 % at 100 mg and 18 % at 200 mg) in AUCτ at steady state compared with first-dose AUC∞ was observed, suggesting that mirabegron may exhibit non-linear pharmacokinetics over time (i.e., an increase in bioavailability and/or a decrease in clearance with time) at these doses. Similar deviations from linear pharmacokinetics (ranging from a 6 % increase at 100 mg to 38 % increase at 300 mg) were observed in a multiple-dose pharmacokinetics study in healthy non-Japanese individuals . As mirabegron exhibited linear pharmacokinetics with time at a clinically relevant dose of 50 mg , the clinical meaningfulness of the finding is likely to be limited.
Comparison of single-dose mean plasma exposure of mirabegron in healthy Japanese and Western (non-Japanese) male subjects
Body weight (kg)
Weight-corrected Cmax (ng/mL·kg)
Weight-corrected AUC∞ (ng·h/mL·kg)
Mirabegron was well-tolerated in healthy Japanese subjects. No serious AEs or discontinuations as a result of AEs were reported at any dose of mirabegron administered in either study. These tolerability findings are consistent with single- and multiple-dose studies conducted in non-Japanese, predominantly Caucasian, healthy subjects at single doses of mirabegron up to 300 mg or multiple daily doses of up to 300 mg [7, 8]. The most common AEs were increased pulse rate in Study 1, and the pulse rate tended to increase dose dependently. These trends are reported by Krauwinkel et al. .
Mirabegron exhibited a greater than dose-proportional increase in exposure after single and multiple oral doses of mirabegron OCAS in healthy Japanese male subjects. Steady-state conditions were reached by 7 days of once-daily administration, and accumulation of mirabegron was about twofold. The single- and multiple-dose pharmacokinetic characteristics and deviations from dose proportionality in healthy Japanese male subjects were similar to those observed in non-Japanese (primarily Caucasian) subjects in previous studies.
The studies were sponsored by Astellas Pharma Inc. The authors thank Virginie Kerbusch, PhD (PharmAspire Consulting) for scientific writing support, for which she received financial compensation from Astellas. Drs. Tokuno, Matsushima, Katashima, Sawamoto, Takusagawa, and Van Gelderen, and Ms. Iitsuka and Amada played a substantial role in the design and overall management of the study, and the collection, analysis, and interpretation of data. Drs. Tanaka and Miyahara were involved in data collection. All authors listed were involved in the critical review and revision of the manuscript, and all provided final approval of the content.
Conflict of interest
Drs. Tokuno, Matsushima, Katashima, Sawamoto, Takusagawa, and Van Gelderen, and Ms. Iitsuka and Amada are paid employees of Astellas Pharma. Drs. Tanaka and Miyahara were the primary study investigators, for which they received financial compensation from Astellas. The authors have indicated that they have no other conflicts of interest with regard to the content of this article.
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