A Study to Compare the Actions in the Body of Healthy Subjects of Three Modified Release Formulations of YM178 Under Fasted and Fed Conditions With One Immediate Release Formulation of YM178 Under Fasted Conditions

An Exploratory Open Label, Three-way Crossover Study to Compare the Pharmacokinetic Profiles of Three Different YM178 Modified Release (OCAS) Formulations Under Fasted and Fed Conditions With YM178 Immediate Release (IR) Formulation Under Fasted Conditions in Healthy Subjects

The purpose of the study is to investigate how quickly and to what extent YM178 is absorbed and eliminated from the body, and how well it is tolerated, when given in three different tablet formulations (sustained release) once a day with and without food, and to compare the results with the profile of the YM178 immediate release formulation taken twice daily without food.

Study Overview

• Status: Completed
• Conditions: Healthy Subjects; Pharmacokinetics of YM178
• Intervention / Treatment: Drug: YM178 modified release (OCAS); Drug: YM178 immediate release (IR)

Detailed Description

Subjects reside in the clinical research unit for 3 periods of 11 days each, with a washout period of at least 7 days between treatment periods. . Each subject is treated with multiple oral doses of the IR formulation (b.i.d.) under fasted conditions and, OCAS-F, OCAS-M or OCAS-S formulation (q.d.) under fasted and fed conditions (high fat breakfast).

The study is completed with a post-study visit between 7 and 14 days after discharge of period 3.

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Zuidlaren, Netherlands, 9471 GP
    • Pharma Bio-Research B.V.

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:

• Body weight between 60.0 and 100.0 kg, and BMI between 18.0 and 30.0 kg/m2

Exclusion Criteria:

• Known or suspected hypersensitivity to β-adrenergic receptor agonists or constituents of the formulations used
• Clinically significant elevation of serum creatinine or liver enzymes as evidenced by creatinine and/or abnormal serum bilirubin
• 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 in the 4 weeks prior to the first 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
• QTcB interval of >430 msec at screening (mean QTcB of two measurements>430msec)
• Abnormal pulse rate measurement (<40 or >90 bpm) 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 minutes
• Positive orthostatic test at screening i.e. any symptoms of dizziness, light-headedness etc. and a fall of > 20 mmHg in systolic blood pressure after 2 min standing (as outlined in section 12.5) and an increase in pulse rate of ≥ 20 bpm
• History of smoking more than 10 cigarettes (or equivalent amount of tobacco) per day within 3 months prior to first admission to the Research Unit.
• History of drinking more than 21 units of alcohol per week within 3 months prior to first admission to the Research Unit
• Donation of blood or blood products (more than 400 ml) within 3 months prior to first admission to the Research Unit or plasmapheresis within 4 weeks preceding the start of this study
• Positive serology test for HBsAg, HAV IgM, anti-HCV or anti-HIV 1+2
• Subject who is not willing to complete standard FDA high fat breakfast

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: OCAS-F; YM178 OCAS tablet (OCAS-Fast) taken orally under fasted and fed condition	Drug: YM178 modified release (OCAS); oral; Other Names: Myrebtriq; mirabegron; Drug: YM178 immediate release (IR); oral; Other Names: Myrebtriq; mirabegron
EXPERIMENTAL: OCAS-S; YM178 OCAS tablet (OCAS-Slow) taken orally under fasted and fed condition	Drug: YM178 modified release (OCAS); oral; Other Names: Myrebtriq; mirabegron; Drug: YM178 immediate release (IR); oral; Other Names: Myrebtriq; mirabegron
EXPERIMENTAL: OCAS-M; YM178 OCAS tablet (OCAS-Medium) taken orally under fasted and fed condition	Drug: YM178 modified release (OCAS); oral; Other Names: Myrebtriq; mirabegron; Drug: YM178 immediate release (IR); oral; Other Names: Myrebtriq; mirabegron

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics profile of OCAS and IR assessed by plasma concentration	AUC0-12h (Area under the plasma concentration - time curve from t=0 to t=12h) Cmax (Maximum concentration), tmax (Time to attain Cmax) and Ctrough (Pre-dose plasma concentration)	Day 1 & Day 6 - Day 8
Pharmacokinetics profile of OCAS assessed by plasma concentration	AUC0-24h (Area under the plasma concentration - time curve from t=0 to t=24h) Cmax, Tmax and Ctrough	Day 8
Pharmacokinetics profile of IR assessed by plasma concentration	AUC0-12h , AUC12-24h (Area under the plasma concentration - time curve from t=12 to t=24h), AUC0-24h, PTR (Peak trough ratio), Cmax, Tmax and Ctrough	Day 8

Secondary Outcome Measures

Outcome Measure	Time Frame
Monitoring of safety parameters through assessment of vital signs, adverse events, Electrocardiogram (ECG) and clinical laboratory assessments	Baseline until Post Study Visit

Collaborators and Investigators

• Sponsor: Astellas Pharma Europe B.V.

Publications and helpful links

General Publications

• Lee J, Zhang W, Moy S, Kowalski D, Kerbusch V, van Gelderen M, Sawamoto T, Grunenberg N, Keirns J. Effects of food intake on the pharmacokinetic properties of mirabegron oral controlled-absorption system: a single-dose, randomized, crossover study in healthy adults. Clin Ther. 2013 Mar;35(3):333-41. doi: 10.1016/j.clinthera.2013.02.014.

Helpful Links

• Link to Results on JAPIC

Study record dates

Study Major Dates

• Study Start: January 1, 2005
• Primary Completion (ACTUAL): May 1, 2005
• Study Completion (ACTUAL): May 1, 2005

Study Registration Dates

• First Submitted: July 18, 2012
• First Submitted That Met QC Criteria: July 18, 2012
• First Posted (ESTIMATE): July 20, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): July 2, 2013
• Last Update Submitted That Met QC Criteria: July 1, 2013
• Last Verified: July 1, 2013

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Fed conditions; Phase I; YM178; Modified release (Oral Controlled Absorption System (OCAS)); Immediate release (IR); Fasted conditions
• Additional Relevant MeSH Terms: Pathologic Processes; Disease; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Urological Agents; Adrenergic Agonists; Adrenergic beta-Agonists; Adrenergic beta-3 Receptor Agonists; Mirabegron
• Other Study ID Numbers: 178-CL-030; 2004-003876-12 (EUDRACT_NUMBER)