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Study to Evaluate the Effect of Solifenacin and Mirabegron on the Digoxin Concentrations in Blood in Healthy Subjects

Information source: Astellas Pharma Inc
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Healthy Subjects; Pharmacokinetics; Drug-Drug Interaction (DDI)

Intervention: Mirabegron (Drug); Solifenacin (Drug); Digoxin (Drug)

Phase: Phase 1

Status: Completed

Sponsored by: Astellas Pharma Europe B.V.

Official(s) and/or principal investigator(s):
Clinical Research Physician, Study Director, Affiliation: Astellas Pharma Europe B.V.

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.

Clinical Details

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 design: Allocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Basic Science

Primary outcome:

Pharmacokinetic parameter for digoxin (plasma) in the absence and presence of solifenacin and mirabegron: Cmax

Pharmacokinetic parameter for digoxin (plasma) in the absence and presence of solifenacin and mirabegron: AUCtau

Secondary outcome:

Pharmacokinetic parameter for digoxin (plasma): Ctrough

Pharmacokinetic parameter for digoxin (plasma): tmax, CL/F, PTR

Pharmacokinetic parameter for digoxin (urine): Aetau, CLR, Aetau%

Pharmacokinetic parameter for solifenacin and mirabegron (plasma): Ctrough

Pharmacokinetic parameter for solifenacin and mirabegron (plasma): Cmax, AUCtau, tmax, CL/F

Pharmacokinetic parameter for solifenacin and mirabegron (plasma): Cpredose

Genotyping for CYP2D6

Safety as assessed by adverse events, physical examination, vital signs, 12-lead ECG and laboratory tests

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

Minimum age: 18 Years. Maximum age: 55 Years. Gender(s): Both.

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.

Locations and Contacts

Parexel International GmbH, Berlin 14050, Germany
Additional Information

Starting date: March 2014
Last updated: July 9, 2014

Page last updated: August 23, 2015

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