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

AbstractPurposeThe objective of these studies was to evaluate the pharmacokinetic profile, safety, and tolerability of mirabegron, a β3-adrenoceptor agonist for the treatment of overactive bladder, including food effects (low- or high-fat meals) and sex, in healthy East Asian subjects.MethodsIn total, 5 pharmacokinetic studies of mirabegron were conducted in healthy East Asian subjects. Food effects were assessed in 3 randomized, single-dose studies in young Japanese male subjects (study 1), male and female subjects (study 2), and young Taiwanese male and female subjects (study 3). In the other 2 single- and multiple-dose studies in young Chinese male and female subjects (study 4 and study 5), mirabegron was administered as a single dose under fasted conditions. After the washout period, mirabegron was administered once daily under fed conditions for 8 days. Pharmacokinetic parameters were determined using noncompartmental methods. Safety and tolerability assessments included physical examinations, vital signs, 12-lead ECG, clinical laboratory tests (biochemistry, hematology, and urinalysis), and adverse event monitoring.FindingsAfter administration of single oral doses of mirabegron, exposure under fed conditions was lower than under fasted conditions in Japanese and Taiwanese subjects. In Japanese subjects, a greater reduction in mirabegron Cmax and AUC0–∞ was observed after a low-fat meal compared with a high-fat meal. In Chinese subjects, Cmax was reached at approximately 4.0 hours after single oral doses. Mirabegron accumulated 2- to 3-fold on once-daily dosing of multiple-dose relative to single-dose data. Steady state was reached within 7 days. After administration of mirabegron, mean values for Cmax and AUC in female subjects were higher than those in male subjects. Mirabegron was well tolerated in Japanese, Taiwanese, and Chinese subjects.ImplicationsOur studies confirm the higher exposure levels of mirabegron in female compared with male East Asian subjects as found earlier in Western subjects. Furthermore, the effects of food on the pharmacokinetic profiles appeared to be similar among the 3 populations tested in our studies. The findings suggest that there are no significant pharmacokinetic differences among the Japanese, Taiwanese, and Chinese populations

Pharmacokinetics of Mirabegron, a β3-Adrenoceptor Agonist for Treatment of Overactive Bladder, in Healthy Japanese Male Subjects: Results from Single- and Multiple-Dose Studies

BACKGROUND: Mirabegron is a human β(3)-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

Detection of Ancestry Informative HLA Alleles Confirms the Admixed Origins of Japanese Population

<div><p>The polymorphisms in the human leukocyte antigen (HLA) region are powerful tool for studying human evolutionary processes. We investigated genetic structure of Japanese by using five-locus HLA genotypes (<i>HLA-A</i>, <i>-B</i>, <i>-C</i>, <i>-DRB1</i>, and <i>-DPB1</i>) of 2,005 individuals from 10 regions of Japan. We found a significant level of population substructure in Japanese; particularly the differentiation between Okinawa Island and mainland Japanese. By using a plot of the principal component scores, we identified ancestry informative alleles associated with the underlying population substructure. We examined extent of linkage disequilibrium (LD) between pairs of HLA alleles on the haplotypes that were differentiated among regions. The LDs were strong and weak for pairs of HLA alleles characterized by low and high frequencies in Okinawa Island, respectively. The five-locus haplotypes whose alleles exhibit strong LD were unique to Japanese and South Korean, suggesting that these haplotypes had been recently derived from the Korean Peninsula. The alleles characterized by high frequency in Japanese compared to South Korean formed segmented three-locus haplotype that was commonly found in Aleuts, Eskimos, and North- and Meso-Americans but not observed in Korean and Chinese. The serologically equivalent haplotype was found in Orchid Island in Taiwan, Mongol, Siberia, and Arctic regions. It suggests that early Japanese who existed prior to the migration wave from the Korean Peninsula shared ancestry with northern Asian who moved to the New World via the Bering Strait land bridge. These results may support the admixture model for peopling of Japanese Archipelago.</p> </div

Principal component analysis of Japanese and South Korean.

<p>A) PCA plot. B) PCS plot. The allele frequencies of South Korean were retrieved from the literatures <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060793#pone.0060793-Lee1" target="_blank">[21]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060793#pone.0060793-Song1" target="_blank">[61]</a>. Dotted lines correspond to mean ± one standard deviation of PCSs. HLA alleles that are labeled and in a circle shows high frequency in Japanese but low frequency in South Korean (referred to as cluster 5 [CL5]; <i>A*24:02</i>, <i>C*03:04</i>, <i>C*07:02</i>, <i>B*40:02</i>, and <i>DRB1*09:01</i>). Alleles shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060793#pone-0060793-g003" target="_blank">Figure 3</a> are also labeled.</p

Baseline characteristics of HLA genotyping for the study participants stratified by district.

<p>Baseline characteristics of HLA genotyping for the study participants stratified by district.</p

The 10 most common five-locus HLA haplotypes in mainland Japanese.

†<p>Nine mainland groups (Hokkaido, Tohoku, Kanto, Hokuriku, Tokai, Kinki, Chugoku, Shikoku, and Kyushu) were combined.</p

Principal component analysis of 10 regional populations in Japan based on allele frequencies of five HLA loci.

<p>A) PCA plot, in which 10 Japanese district populations are plotted according to their corresponding eigenvectors of first and second principal components. B) PCS plot, in which HLA alleles are plotted according to their first and second principal component scores. Dotted lines correspond to mean ± one standard deviation of PCSs. HLA alleles whose absolute PCSs were greater than one standard deviation were selected, followed by Fisher's exact test to evaluate whether the allele frequencies were differentiated among regions. HLA alleles showing significant differentiation at <i>P</i><0.001 are determined as “ancestry informative HLA alleles” and labeled in the plot. The frequency distribution of the identified HLA alleles shows distinct patterns (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060793#pone-0060793-g003" target="_blank">Figure 3</a>). The HLA alleles showing similar pattern of differentiation are co-localized in the PCS plot. We marked HLA alleles showing similar patterns of differentiation (referred to as CL1-4) by circles.</p