To Compare Blood and Urine Concentrations of Mirabegron (YM178) in Healthy Poor or Extensive Metabolizers for CYP2D6 and to Assess the Effect of Mirabegron on the Metabolism of Metoprolol

An Open Label, One-sequence, Parallel Study to Compare the Single Dose Pharmacokinetics of YM178 in Healthy Poor or Extensive Metabolisers for CYP2D6 and to Assess the Effect of Multiple Doses of YM178 on the Metabolism of the Model Substrate Metoprolol

The study aims to compare blood and urine concentrations of mirabegron (YM178) in healthy poor or extensive metabolizers for CYP2D6 and to evaluate if blood levels of metoprolol change whilst being dosed at the same time with daily miragebron.

Study Overview

• Status: Completed
• Conditions: Healthy Subjects; Pharmacokinetics of Mirabegron
• Intervention / Treatment: Drug: mirabegron; Drug: metoprolol

Detailed Description

The study is an open label, single center study. All subjects are genotyped for CYP2D6 before the study. Genotype expression is confirmed by dextromethorphan phenotyping.

Part I: The pharmacokinetic profile of a single dose of YM178 is compared in 8 healthy male subjects genotyped and phenotyped as poor metaboliser (PM) for CYP2D6 and in 8 healthy male subjects genotyped and phenotyped as extensive metaboliser (EM) for CYP2D6.

Part II: The effect of YM178 on the model substrate of CYP2D6 metoprolol is evaluated, using a cross-over design, in 12 healthy male subjects genotyped and phenotyped as EM for CYP2D6.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Zuidlaren, Netherlands, 9471 GP
    • PRA International (former Pharma Bio-Research)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

For Part I:

• Subject genotyped and phenotyped for CYP2D6
• Body weight between 60 and 100 kg and Body Mass Index less than or equal to 30 kg/m2

For Part II:

• Subject genotyped and phenotyped as extensive metaboliser for CYP2D6
• Body weight between 60 and 100 kg and Body Mass Index less than or equal to 30 kg/m2

Exclusion Criteria:

• Known or suspected hypersensitivity to β-adrenergic receptor agonists or constituents of the formulations used
• Any clinically significant history of asthma, eczema, any other allergic condition or previous severe hypersensitivity to any drug
• Any clinically significant history of upper gastrointestinal symptoms (such as nausea, vomiting, abdominal discomfort or upset, or heartburn) in the 4 weeks prior to admission to the Research Unit
• Any clinically significant history of any other disease or disorder - gastrointestinal, cardiovascular, respiratory, renal, hepatic, neurological, dermatological, psychiatric or metabolic
• Any clinically significant abnormality following the investigator's review of the pre-study physical examination, ECG and clinical laboratory tests
• QTc intervals of >430 msec
• Abnormal pulse rate measurement (<40 or >90 bpm) taken by manual counting at the pre-study visit after subject has been resting in supine position for 5 min
• Abnormal blood pressure measurements taken at the pre-study visit after subject has been resting in supine position for 5 min as follows: systolic blood pressure <95 or >160 mmHg; diastolic blood pressure <40 or >95 mmHg
• Positive orthostatic test at screening i.e. any symptoms of dizziness, light-headedness etc. and/or a fall of ≥ 20 mmHg in systolic blood pressure after 2 min standing (preceded by 5 min. supine rest) and/or an increase in pulse rate of ≥ 20 bpm
• Regular use of any prescribed or OTC drugs except paracetamol up to 3 g/day, in the 4 weeks prior to admission to the Research Unit OR any use of such drugs in the 2 weeks prior to admission to the Research Unit

Study Plan

How is the study designed?

Design Details

• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Arm 1A; mirabegron, poor metabolizers	Drug: mirabegron; oral; Other Names: YM178
Experimental: Treatment Arm 1B; mirabegron, extensive metabolizers	Drug: mirabegron; oral; Other Names: YM178
Experimental: Treatment Arm 2; mirabegron/metoprolol	Drug: mirabegron; oral; Other Names: YM178; Drug: metoprolol; oral

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics of mirabegron assessed by plasma concentration	Primary outcome measure for Part 1	Pre-dose until 72 hours after dosing

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics of metoprolol assessed by plasma concentration	Primary outcome measure for Part 2	Pre-dose until 48 hours after dosing

Collaborators and Investigators

• Sponsor: Astellas Pharma Inc
• Investigators: Principal Investigator: Principal Investigator, Pharma Bio-Research Group B.V., Zuidlaren, The Netherlands

Publications and helpful links

General Publications

• Krauwinkel W, Dickinson J, Schaddelee M, Meijer J, Tretter R, van de Wetering J, Strabach G, van Gelderen M. The effect of mirabegron, a potent and selective beta3-adrenoceptor agonist, on the pharmacokinetics of CYP2D6 substrates desipramine and metoprolol. Eur J Drug Metab Pharmacokinet. 2014 Mar;39(1):43-52. doi: 10.1007/s13318-013-0133-1. Epub 2013 Jun 1.

Helpful Links

• Link to Results on JAPIC

Study record dates

Study Major Dates

• Study Start: September 1, 2002
• Primary Completion (Actual): November 1, 2002
• Study Completion (Actual): November 1, 2002

Study Registration Dates

• First Submitted: November 21, 2011
• First Submitted That Met QC Criteria: November 21, 2011
• First Posted (Estimate): November 23, 2011

Study Record Updates

• Last Update Posted (Estimate): April 10, 2014
• Last Update Submitted That Met QC Criteria: April 8, 2014
• Last Verified: November 1, 2011

More Information

Terms related to this study

• Keywords: Phase 1; Mirabegron; Pharmacokinetics,; CYP2D6; Metoprolol
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Autonomic Agents; Peripheral Nervous System Agents; Urological Agents; Adrenergic Agonists; Adrenergic beta-Agonists; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Adrenergic beta-3 Receptor Agonists; Metoprolol; Mirabegron
• Other Study ID Numbers: 178-CL-005