Clinical trial NCT01478490: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Pharmacokinetics of Mirabegron
Healthy Subjects
Keywords: Pharmacokinetics,
Mirabegron
Metoprolol
CYP2D6
Phase 1
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2011-11-23
Enrollment: 28
Sex: MALE
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER

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.

Eligibility criteria: 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

Primary outcomes:
measure: Pharmacokinetics of mirabegron assessed by plasma concentration
timeFrame: Pre-dose until 72 hours after dosing
Secondary outcomes:
measure: Pharmacokinetics of metoprolol assessed by plasma concentration
timeFrame: Pre-dose until 48 hours after dosing
Other outcomes:
Locations:
city: Zuidlaren
country: Netherlands
facility: PRA International (former Pharma Bio-Research)
Study officials:
affiliation: Astellas Pharma Europe B.V.
name: Clinical Study Manager
role: STUDY_CHAIR
affiliation: Pharma Bio-Research Group B.V., Zuidlaren, The Netherlands
name: Principal Investigator
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.