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

Healthy Subjects Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01478490
• Other study ID #: 178-CL-005
• Status: Completed
• Phase: Phase 1
• First received: November 21, 2011
• Last updated: April 8, 2014
• Start date: September 2002
• Est. completion date: November 2002

Study information

• Verified date: November 2011
• Source: Astellas Pharma Inc
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationNetherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 28
• Est. completion date: November 2002
• Est. primary completion date: November 2002
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 55 Years

Eligibility

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 ß-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

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Crossover Assignment, Masking: Open Label

Related Conditions & MeSH terms

• Healthy Subjects
• Pharmacokinetics of Mirabegron

Intervention

Drug:
• mirabegron
oral
• metoprolol
oral

Locations

Country	Name	City	State
Netherlands	PRA International (former Pharma Bio-Research)	Zuidlaren

Sponsors (1)

Lead Sponsor	Collaborator
Astellas Pharma Inc

Country where clinical trial is conducted

Netherlands, 

References & Publications (1)

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 ß3-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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pharmacokinetics of mirabegron assessed by plasma concentration	Primary outcome measure for Part 1	Pre-dose until 72 hours after dosing	No
Secondary	Pharmacokinetics of metoprolol assessed by plasma concentration	Primary outcome measure for Part 2	Pre-dose until 48 hours after dosing	No

External Links

•   Link to Results on JAPIC