An Exploratory Study in Healthy Male Subjects of the Mechanism of Mirabegron-Induced Cardiovascular Effects.

To explore the role of β -adrenoceptors (ARs) in the heart rate response to the selective β -adrenoceptor agonist mirabegron, 12 young male volunteers received single oral doses of the nonselective β -AR antagonist propranolol (160 mg), the selective β -AR antagonist bisoprolol (10 mg), or placebo on days 1 and 5 of each period in a 3-period crossover study. On day 5, dosing was followed by a supratherapeutic dose of mirabegron (200 mg). Vital signs, impedance cardiography, and plasma renin activity were collected.

Pharmacokinetic Interactions Between Mirabegron and Metformin, Warfarin, Digoxin or Combined Oral Contraceptives.

Background And Objectives: Mirabeg ron is a selective β3-adrenoceptor agonist approved for the treatment of overactive bladder (OAB). Four phase 1 studies were conducted in healthy subjects to evaluate the potential for pharmacokinetic interactions between mirabegron and metformin, warfarin, digoxin, or a combination oral contraceptive (COC).

Methods: Thirty-two male subjects received metformin (500 mg twice daily) or mirabegron (160 mg once daily) alone, in combination or with placebo.

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

Purpose: The 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.

Methods: In 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).

Reproducibility of QTc interval changes after meal intake.

Background: Detection of QTc decreases after meal intake was proposed as a possible proof of assay sensitivity in studies of drug-induced QTc changes. However, day-to-day reproducibility of QTc decreases after meal intake has not been established.

Methods: Holter recordings were available from 4 different baseline drug-free days of a thorough QT study in 157 females and 164 males.

QTc changes after meal intake: sex differences and correlates.

Background: Detection of food-induced QTc shortening has been proposed as an assay sensitivity in thorough QT/QTc (TQT) studies. Data of a large clinical study were used to investigate the food effects on QTc intervals.

Methods: Day-time drug-free 12-lead Holter recordings starting around 8:20AM were repeated 4 times in each of 176 female and 176 male healthy subjects aged 32.

ICH E14-compatible holter bin method and its equivalence to individual heart rate correction in the assessment of drug-induced QT changes.

Introduction: The Holter bin method evaluates QT interval changes in the presence of heart rate changes without correcting the QT interval. However, the method does not allow time-matched comparisons, thus contradicting available guidance and good practice. We report a modification of the methods that allows time-matched comparisons without any heart rate correction.

Absence of clinically relevant cardiovascular interaction upon add-on of mirabegron or tamsulosin to an established tamsulosin or mirabegron treatment in healthy middle-aged to elderly men.

Objective: Tamsulosin and mirabegron may be used concomitantly in patients with lower urinary tract symptoms. Since alpha1-adrenoceptor antagonists are associated with cardiovascular side effects, potential pharmacokinetic and cardiovascular interactions were evaluated.

Materials And Methods: This was an open-label, randomized, 2-arm, 2-sequence study in 48 healthy men (24/arm) aged 44 - 72 years.

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 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.

QT/RR curvatures in healthy subjects: sex differences and covariates.

Data of a large clinical study were used to investigate how much are the QT/RR patterns in healthy subjects curved and whether these curvatures differ between women and men. Daytime drug-free 12-lead Holter recordings were repeated 4 times in each of 176 female healthy subjects and 176 male healthy subjects aged 32.7 ± 9.

Relationship of QT interval variability to heart rate and RR interval variability.

The study investigated whether the beat-to-beat QT interval variability relationship to the mean heart rate and the RR interval variability depended on the cardiovascular autonomic status changed by postural positioning. Repeated long-term 12-lead Holter recordings were obtained from 352 healthy subjects (mean age 32.7 ± 9.

Evaluation of the Pharmacokinetic Interaction Between the β3 -Adrenoceptor Agonist Mirabegron and the Muscarinic Receptor Antagonist Solifenacin In Healthy Subjects.

Mirabegron, a selective β3 -adrenoceptor agonist, is approved for the treatment of overactive bladder (OAB). Solifenacin is a muscarinic receptor antagonist widely used in the treatment of OAB. This open-label, 1-sequence, 2-arm study investigated whether any pharmacokinetic interaction exists between mirabegron and solifenacin.

The effect of mirabegron, a potent and selective β3-adrenoceptor agonist, on the pharmacokinetics of CYP2D6 substrates desipramine and metoprolol.

Mirabegron is a potent and selective β3-adrenoceptor agonist developed for the treatment of overactive bladder. In vitro studies demonstrated that mirabegron partly acts as a (quasi-) irreversible, metabolism-dependent inhibitor of CYP2D6. The effect of steady-state mirabegron on single doses of the sensitive CYP2D6 substrates metoprolol (100 mg) and desipramine (50 mg) was assessed in two open-label, one-sequence crossover studies in healthy subjects (CYP2D6 extensive metabolizers).

Role of cytochrome p450 isoenzymes 3A and 2D6 in the in vivo metabolism of mirabegron, a β3-adrenoceptor agonist.

Background: Mirabegron is a β3-adrenoceptor agonist for the treatment of overactive bladder. There has been little information published or presented about the involvement of cytochrome P450 (CYP) isoenzymes 3A and 2D6 in the metabolism of mirabegron in humans; in vitro data indicate that oxidative metabolism is primarily mediated by CYP3A with a minor role for CYP2D6.

Objective: To determine to what extent CYP3A and CYP2D6 isoenzymes are involved in mirabegron metabolism.

Effects of food intake on the pharmacokinetic properties of mirabegron oral controlled-absorption system: a single-dose, randomized, crossover study in healthy adults.

Background: Mirabegron is a β3-adrenoceptor agonist used for the treatment of overactive bladder. Mirabegron is formulated as an extended-release tablet using oral controlled-absorption system (OCAS) technology.

Objective: This study was designed to assess the effects of food on the pharmacokinetic properties of mirabegron OCAS in accordance with regulatory requirements to support dosing recommendations.

Effect of renal or hepatic impairment on the pharmacokinetics of mirabegron.

Background And Objectives: Mirabegron, a selective β3-adrenoceptor agonist for the treatment of overactive bladder (OAB), is eliminated by renal and metabolic routes. The potential influence of renal or hepatic impairment on the pharmacokinetics of mirabegron was evaluated.

Methods: Two separate open-label, single-dose, parallel-group studies were conducted.

Pharmacokinetic properties of mirabegron, a β3-adrenoceptor agonist: results from two phase I, randomized, multiple-dose studies in healthy young and elderly men and women.

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.

Importance of subject-specific QT/RR curvatures in the design of individual heart rate corrections of the QT interval.

Objective: A statistical modelling study investigated whether incorporating the curvatures of QT/RR patterns into the individual-specific QT heart rate correction increases QTc data accuracy.

Methods: Repeated ECG readings were available from 4 different drug-free recordings made in 176+176 healthy female and male subjects (aged 32 ± 10 and 33 ± 8 years, respectively). In each subject, up to 1440 ECG readings were made of QT intervals and of the corresponding QT/RR hysteresis corrected RR intervals.

Single dose pharmacokinetics and absolute bioavailability of mirabegron, a β₃-adrenoceptor agonist for treatment of overactive bladder.

Background And Objectives: Mirabegron is a potent and selective β3-adrenoceptor agonist in development for treatment of overactive bladder.

Methods: Mirabegron pharmacokinetics after single intravenous (i.v.

Development and validation of LC-MS/MS methods for the determination of mirabegron and its metabolites in human plasma and their application to a clinical pharmacokinetic study.

Mirabegron is being developed for the treatment of overactive bladder. To support the development of mirabegron, including pharmacokinetic studies, liquid chromatography/tandem mass spectrometry methods for mirabegron and eight metabolites (M5, M8, M11-M16) were developed and validated for heparinized human plasma containing sodium fluoride. Four separate bioanalytical methods were developed for the analysis of: (1) mirabegron; (2) M5 and M16; (3) M8; and (4) M11-M15.

Absorption, metabolism and excretion of [(14)C]mirabegron (YM178), a potent and selective β(3)-adrenoceptor agonist, after oral administration to healthy male volunteers.

The mass balance and metabolite profiles of 2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)[U-(14)C]phenyl]acetamide ([(14)C]mirabegron, YM178), a β(3)-adrenoceptor agonist for the treatment of overactive bladder, were characterized in four young, healthy, fasted male subjects after a single oral dose of [(14)C]mirabegron (160 mg, 1.85 MBq) in a solution. [(14)C]Mirabegron was rapidly absorbed with a plasma t(max) for mirabegron and total radioactivity of 1.

An example of optimal phase II design for exposure response modelling.

This paper presents an example of how optimal design methodology was used to help design a phase II clinical study. The planned analysis would relate the clinical endpoint to exposure (measured via the area under the curve (AUC)), rather than dose. Optimal design methodology was used to compare a number of candidate phase II designs, and an algorithm for finding optimal designs was employed.

Haemodynamic changes and acetylcholine-induced hypotensive responses after NG-nitro-L-arginine methyl ester in rats and cats.

1. The haemodynamic effects of NG-nitro-L-arginine methylester (L-NAME; 1, 3, 10 and 30 mg kg-1) and its potential ability to attenuate the hypotensive responses to acetylcholine (0.03, 0.