Clinical trial NCT02127034: Study to Evaluate the Effect of Solifenacin and Mirabegron on the Digoxin Concentrations in Blood in Healthy Subjects
Official title: A Phase 1 Study to Evaluate the Effect of Steady State Solifenacin and Mirabegron on the Steady State Pharmacokinetics of Digoxin in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Subjects
Pharmacokinetics
Drug-Drug Interaction (DDI)
Keywords: Healthy subjects
Mirabegron
Solifenacin
Digoxin
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2014-04-30
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: The purpose of this study is to evaluate the effect of steady state solifenacin and mirabegron on the pharmacokinetics of co-administered steady state digoxin. This study will also evaluate the safety and tolerability of the combined steady state administration of solifenacin, mirabegron and digoxin.

Detailed description: This study is comprised of two study sequences with 2 investigational periods in each sequence. There will be a wash-out period between each investigational period. Patients will be admitted to the clinic until discharged after each investigational period.

Eligibility criteria: Inclusion Criteria:

* Subject has a body mass index range of 20.0 to 30.0 kg/m2, inclusive. The subject weighs at least 50 kg \[screening\].
* Female subject must either:

  * Be of non-child bearing potential:

    1. post-menopausal (defined as at least 1 year without any menses) prior to screening, or
    2. documented surgically sterile
  * Or, if of childbearing potential,

    1. Agree not to try to become pregnant during the clinical study and for 28 days after the final study drug administration, and
    2. must have a negative urine/serum pregnancy test at screening and day -1,and
    3. if heterosexually active, agree to consistently use 2 forms of highly effective birth control starting at screening and throughout the clinical study period and for 28 days after the final study drug administration.
* Female subject must agree not to breastfeed starting at screening and throughout the clinical study period, and for 28 days after the final study drug administration.
* Female subject must not donate ova starting at screening and throughout the clinical study period, and for 28 days after the final study drug administration.
* Male subject and their female spouse/partners who are of childbearing potential must be using a highly effective form of contraception consisting of 2 forms of birth control (1 of which must be a barrier method) starting at screening and continue throughout the clinical study period and for 90 days after the final study drug administration.
* Male subject must not donate sperm starting at screening and throughout the clinical study period and for 90 days after the final study drug administration
* Subject agrees not to participate in another interventional study while participating in the present clinical study, defined as signing the informed consent form (ICF) until completion of the last study visit.

Exclusion Criteria:

* Female subject who has been pregnant within 6 months prior to screening assessment or breast feeding within 3 months prior to screening.
* Subject has a known or suspected hypersensitivity to solifenacin succinate, mirabegron, digoxin or any components of the formulations used.
* Subject has any of the liver function tests (LFTs) (aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\], alkaline phosphatase \[ALP\], GGT, total bilirubin \[TBL\]) above the upper limit of normal (ULN). In such a case the assessment may be repeated once \[day -1\].
* Subject has any clinically significant history of allergic conditions.
* Subject has/had febrile illness or symptomatic, viral, bacterial (including upper respiratory infection), or fungal (non-cutaneous) infection within 1 week prior to day -1.
* Subject has any clinically significant abnormality following the Investigator's review of the physical examination, ECG (e.g., any level of sinus node disease or atrioventricular defect) and protocol defined clinical laboratory tests (e.g., electrolyte abnormalities such as hypokalemia) at screening or day -1.
* Subject has any history or evidence of any clinically significant cardiovascular, gastrointestinal, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, and/or other major disease or malignancy, as judged by the medical Investigator.
* Subject has a mean heart rate (HR) of \< 50 or \> 90 beats per minute (bpm); mean systolic BP \>140 mmHg; mean diastolic BP \> 90 mmHg at day-1 (vital sign measurements taken in triplicate after subject has been resting in supine position for 5 min; pulse will be measured automatically).
* Subject has a mean QTc(F) interval of \> 430 ms (for males) and \> 450 ms (for females) at day-1. If the mean QTc(F) exceeds the limits above, 1 additional triplicate ECG can be taken. If this triplicate also gives abnormal result the subject should be excluded.
* Subject has a history of unexplained syncope, cardiac arrest, unexplained cardiac arrhythmias or torsade de pointes, structural heart disease, or a family history of Long QT Syndrome.
* Subject has any clinically significant history of or risk of urinary retention, severe gastrointestinal condition (including toxic megacolon), myasthenia gravis or narrow-angle glaucoma.
* Subject uses any prescribed or non-prescribed drugs (including vitamins, hormone replacement therapy or natural and herbal remedies \[e.g., St. John's Wort\]) in the 2 weeks prior to study drug administration, except for occasional use of paracetamol (up to 2 g/day).
* Subject has a history of smoking more than 10 cigarettes (or equivalent amount of tobacco) per day within 3 months prior to admission to the clinical unit.
* Subject has a history of drinking more than 21 units (14 units for females) of alcohol per week (1 unit = 10 g pure alcohol = 250 mL of beer \[5\] or 35 mL of spirits \[35%\] or 100 mL of wine \[12%\]) within 3 months prior to admission to the clinical unit.
* Subject consumes grapefruit juice (more than 3 x 200 mL) or marmalade (more than 3 times) star fruit, Seville oranges or Seville orange juice containing products in the week prior to admission to the clinical unit until end of study visit (ESV), as reported by the subject.
* Subject uses any drugs of abuse within 3 months prior to admission to the clinical unit.
* Subject regularly uses of any inducer of metabolism (e.g., barbiturates, rifampin) in the 3 months prior to admission to the clinical unit.
* Subject has significant blood loss, donated 1 unit (500 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.
* Subject has a positive serology test for hepatitis B surface antigen (HBsAg), hepatitis B core (HBc) antibodies, hepatitis A virus (HAV) antibodies (Immunoglobulin M \[IgM\]), hepatitis C virus (HCV) antibodies or human immunodeficiency virus (HIV) 1+2 antibodies.
* Subject participated in any clinical study or has been treated with any investigational drugs within 28 days prior to screening.
* Subject is a vulnerable subject (e.g., subject kept in detention).
* Subject is an employee of the Astellas Group or Contract Research Organization (CRO) involved in the clinical study.

Primary outcomes:
measure: Pharmacokinetic parameter for digoxin (plasma) in the absence and presence of solifenacin and mirabegron: Cmax
timeFrame: Day 10
measure: Pharmacokinetic parameter for digoxin (plasma) in the absence and presence of solifenacin and mirabegron: AUCtau
timeFrame: Day 10
Secondary outcomes:
measure: Pharmacokinetic parameter for digoxin (plasma): Ctrough
timeFrame: Days 7, 8 and 9 in each investigational period
measure: Pharmacokinetic parameter for digoxin (plasma): tmax, CL/F, PTR
timeFrame: Days 10 in each investigational period
measure: Pharmacokinetic parameter for digoxin (urine): Aetau, CLR, Aetau%
timeFrame: Day 10 in each investigational period
measure: Pharmacokinetic parameter for solifenacin and mirabegron (plasma): Ctrough
timeFrame: Days 7, 8 and 9 (1 investigational period per sequence only)
measure: Pharmacokinetic parameter for solifenacin and mirabegron (plasma): Cmax, AUCtau, tmax, CL/F
timeFrame: Day 10 (1 investigational period per sequence only)
measure: Pharmacokinetic parameter for solifenacin and mirabegron (plasma): Cpredose
timeFrame: Day 1 (1 investigational period for only 1 treatment sequence)
measure: Genotyping for CYP2D6
timeFrame: Day 1
measure: Safety as assessed by adverse events, physical examination, vital signs, 12-lead ECG and laboratory tests
timeFrame: Up to Day 11 in each investigational period (and at end of study visit, up to 9 days after)
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Parexel International GmbH
Study officials:
affiliation: Astellas Pharma Europe B.V.
name: Clinical Research Physician
role: STUDY_DIRECTOR
References: