To Evaluate the Effect of Mirabegron (YM178) on Blood Levels of Desipramine When They Are Taken Together

An Open-label, One-sequence Crossover Study to Evaluate the Effect of Multiple Doses of YM178 on the Pharmacokinetics of the CYP2D6 Substrate Desipramine in Healthy Subjects

The study aims to evaluate if blood levels of desipramine change whilst being dosed at the same time with daily mirabegron.

Study Overview

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

Detailed Description

This is an open-label, one-sequence crossover design study to evaluate the drug-drug interaction between mirabegron and desipramine. The effect of mirabegron on the plasma concentration of desipramine will be evaluated after 13 day repeated administration. The recovery of CYP2D6 activity is also being explored by comparing the pharmacokinetic profiles of desipramine after a 2 week wash-out period.

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

Contacts and Locations

Study Locations

• France
  • Paris, France, 75015
    • SGS Aster

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Body Mass Index between 18.5 and 30.0 kg/m2 inclusive
• Subject is genotyped and phenotyped as an extensive metabolizer for CYP2D6

Exclusion Criteria:

• Known or suspected hypersensitivity to YM178 or any of the components of the formulation used
• Known or suspected hypersensitivity to desipramine or any of the components of the formulation used
• Pregnant or breast feeding within 6 months before screening assessment
• Any clinical history of major depressive disorder, cardiovascular disease, urinary retention, glaucoma, thyroid disease and/or seizure disorder
• Any of the liver function tests (i.e. Alanine Aminotransferase (ALT), Asparate Aminotransferase (AST) and Alkaline phosphatase) above the upper limit of normal at repeated measurements
• Any clinically significant history of asthma, eczema, any other allergic condition or previous severe hypersensitivity to any drug (excluding non-active hay fever)
• Any clinically significant abnormality following the investigator's review of the pre-study physical examination, ECG and clinical laboratory tests
• Abnormal pulse rate and/or blood pressure measurements at the pre-study visit as follows: pulse rate <40 or >90 bpm; mean systolic blood pressure >140 mmHg; mean diastolic blood pressure >90 mmHg (blood pressure measurements taken in triplicate after subject has been resting in supine position for 5 min; pulse rate will be measured automatically)
• A marked baseline prolongation of QT/QTc interval after repeated measurements of >450 ms, a history of unexplained syncope, cardiac arrest, unexplained cardiac arrhythmias or torsades de pointes, structural heart disease, or a family history of Long QT Syndrome (LQTS)

Study Plan

How is the study designed?

Design Details

• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: mirabegron / desipramine	Drug: mirabegron; oral; Other Names: YM178; Drug: desipramine; oral; Other Names: pertofrane; norpramin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Pharmacokinetics of desipramine assessed by plasma concentration while at steady state levels of mirabegron	Pre-dose until 72 hours after dosing

Secondary Outcome Measures

Outcome Measure	Time Frame
Monitoring of safety and tolerability through assessment of vital signs, ECG, clinical safety laboratory and adverse events	Baseline until End of Study Visit (7 to 14 days after last dose)
Pharmacokinetics of desipramine assessed by plasma concentration after wash-out of mirabegron	Pre-dose until 72 hours after wash-out

Collaborators and Investigators

• Sponsor: Astellas Pharma Inc

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: October 1, 2008
• Primary Completion (Actual): January 1, 2009
• Study Completion (Actual): January 1, 2009

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: July 1, 2013

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Phase 1; Mirabegron
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Urological Agents; Enzyme Inhibitors; Adrenergic Agonists; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Antidepressive Agents, Tricyclic; Adrenergic beta-Agonists; Adrenergic Uptake Inhibitors; Adrenergic beta-3 Receptor Agonists; Desipramine; Mirabegron
• Other Study ID Numbers: 178-CL-058; 2008-000215-15 (EudraCT Number)