A Study to Compare How Much Solifenacin Succinate and Mirabegron Reach the Blood When Administered Together as Fixed-dose Combination Tablets and With Single Individual Tablets of the Same Medications at Three Dose Levels

An Open-label, Parallel Group, Randomized, Two-sequence, Three-way Crossover Study to Assess the Relative Bioavailability of Solifenacin Succinate and Mirabegron Fixed-dose Combination Tablets Compared to Co-administration of Single Entity Tablets at Three Dose Strengths in Healthy Male and Female Subjects

This study compares the pharmacokinetics (PK), safety and tolerability of fixed dose combination (FDC) tablets containing solifenacin succinate and mirabegron with the co-administration of single entity tablets (SET), at three dose strengths.

Study Overview

• Status: Completed
• Conditions: Healthy Subjects; Bioavailability; Phase 1
• Intervention / Treatment: Drug: mirabegron; Drug: solifenacin succinate; Drug: mirabegron/solifenacin succinate

Detailed Description

There are three parallel groups each with 24 healthy male and female subjects (with a minimum of 10 subjects per gender). Each group receives one dose strength.

The study utilizes a partial replicate cross-over design with three periods and each subject receives the same strength of either the FDC or SET formulation twice.

Screening takes place within 21 days before admission and subjects are admitted on Day -1. Dosing takes place on Day 1, after an overnight fast of at least 10 hours. Subjects remain fasted until 4 hours post-dose. There is a wash-out period of at least 14 days between each dose administration.

Subjects are discharged on Day 4 and return to the clinical unit on Days 5, 6, 7, 9 and 11 for outpatient assessments.

An End-of-Study Visit (ESV) takes place on Day 11 of Period 3 or within 7-14 days after discontinuation.

• Study Type: Interventional
• Enrollment (Actual): 72
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 14050
    • Parexel

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:

• Male subject must agree to not donate semen from the day of first dosing until 3 months after last discharge and practice an effective contraceptive method with female sexual partners to prevent pregnancy.
• Female subject must be of non-child bearing potential, i.e. postmenopausal, surgically sterilized, hysterectomy in medical history, or practicing highly effective non-hormonal birth control.

Exclusion Criteria:

• Female subject who is pregnant, has been pregnant within 6 months before screening or breast-feeding within 3 months before screening.
• Known or suspected hypersensitivity to solifenacin succinate, mirabegron or any components of the formulations used.
• The subject has/had febrile illness or symptomatic, viral, bacterial (including upper respiratory infection), or fungal (non-cutaneous) infection within 1 week prior to admission to the clinical unit.
• Any significant blood loss, donated one unit (450 mL) of blood or more, or received a transfusion of any blood or blood products within 60 days or donated plasma within 7 days prior to clinic admission on Day -1.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 1: FDC-SET-SET; Fixed Dose Combination followed by two periods of the Single Entity Tablets	Drug: mirabegron; oral; Other Names: YM178; Drug: solifenacin succinate; oral; Other Names: YM905; Vesicare®,; Drug: mirabegron/solifenacin succinate; oral; Other Names: YM178/YM905
EXPERIMENTAL: 2: SET-FDC-FDC; Single Entity Tablets followed by two periods of Fixed Dose Combination	Drug: mirabegron; oral; Other Names: YM178; Drug: solifenacin succinate; oral; Other Names: YM905; Vesicare®,; Drug: mirabegron/solifenacin succinate; oral; Other Names: YM178/YM905

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Pharmacokinetic parameter of solifenacin in plasma as measured by Cmax (Maximum concentration)	Days 1-11
Pharmacokinetic parameter of solifenacin in plasma as measured by AUClast (AUC until last sample taken)	Days 1-11
Pharmacokinetic parameter of solifenacin in plasma as measured by AUCinf (AUC extrapolated until infinity)	Days 1-11
Pharmacokinetic parameter of mirabegron in plasma as measured by Cmax (Maximum concentration)	Days 1-11
Pharmacokinetic parameter of mirabegron in plasma as measured by AUClast (AUC until last sample taken)	Days 1-11
Pharmacokinetic parameter of mirabegron in plasma as measured by AUCinf (AUC extrapolated until infinity)	Days 1-11

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic profile of Solifenacin in plasma	AUC0-72h (Area under the plasma concentration-time curve from time zero to 72h), tmax (Time to attain Cmax), tlag (Absorption lag time), t1/2 (Apparent terminal elimination half-life), Vz/F (Apparent volume of distribution), CL/F (Apparent total body plasma clearance)	Days 1-11
Pharmacokinetic profile of mirabegron in plasma	AUC0-72h (Area under the plasma concentration-time curve from time zero to 72h), tmax (Time to attain Cmax), tlag (Absorption lag time), t1/2 (Apparent terminal elimination half-life), Vz/F (Apparent volume of distribution), CL/F (Apparent total body plasma clearance)	Days 1-11
Safety and tolerability of solifenacin succinate and mirabegron assessed by adverse events, vital signs, laboratory tests, physical examination and 12-lead electrocardiogram (ECG)		Screening to End of Study Visit (Day 11 Period 3 or within 7 to 14 days after discontinuation)

Collaborators and Investigators

• Sponsor: Astellas Pharma Europe B.V.

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (ACTUAL): November 1, 2012
• Study Completion (ACTUAL): November 1, 2012

Study Registration Dates

• First Submitted: October 4, 2013
• First Submitted That Met QC Criteria: December 10, 2013
• First Posted (ESTIMATE): December 13, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): December 13, 2013
• Last Update Submitted That Met QC Criteria: December 10, 2013
• Last Verified: October 1, 2013

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Bioavailability; Mirabegron; Fixed-dose combination (FDC); Solifenacin; Single Entity Tablet (SET)
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Urological Agents; Adrenergic Agonists; Adrenergic beta-Agonists; Adrenergic beta-3 Receptor Agonists; Mirabegron; Solifenacin Succinate
• Other Study ID Numbers: 178-CL-103; 2012-002650-23 (EUDRACT_NUMBER)