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

Phase 1

Completed

• Conditions: Pharmacokinetics of Mirabegron; Healthy Subjects
• Interventions: Drug: mirabegron; Drug: metoprolol

• Registration Number: NCT01478490
• Lead Sponsor: Astellas Pharma Inc

Brief Summary

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.

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 Timeline

• Study Start: 2002-09
• Primary Completion: 2002-11
• Study Completion: 2002-11
• Status Verified: 2011-11
• Study First Submitted: 2011-11-21
• Study First Submitted QC: 2011-11-21
• Study First Posted: 2011-11-23
• Last Update Submitted: 2014-04-08
• Last Update Posted: 2014-04-10

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 28

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Treatment Arm 1A	mirabegron	mirabegron, poor metabolizers
Treatment Arm 1B	mirabegron	mirabegron, extensive metabolizers
Treatment Arm 2	mirabegron	mirabegron/metoprolol
Treatment Arm 2	metoprolol	mirabegron/metoprolol

Primary Outcome Measures

Name	Time	Method
Pharmacokinetics of mirabegron assessed by plasma concentration	Pre-dose until 72 hours after dosing	Primary outcome measure for Part 1

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetics of metoprolol assessed by plasma concentration	Pre-dose until 48 hours after dosing	Primary outcome measure for Part 2

Trial Locations

Locations (1)

PRA International (former Pharma Bio-Research); 🇳🇱 Zuidlaren, Netherlands