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Pharmacokinetic Drug Interaction Between Ezetimibe and Tacrolimus After Single Dose Administration in Healthy Subjects

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00621699
First Posted: February 22, 2008
Last Update Posted: February 22, 2008
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by:
University Medicine Greifswald
  Purpose
The purpose of this study is to confirm a significant influence of ezetimibe and tacrolimus on each others pharmacokinetics

Condition Intervention Phase
Pharmacokinetics Drug Interactions Hypercholesterolemia Immunosuppression Drug: 1 tablet Ezetrol(R) (ezetimibe), MSD Sharp & Dohme GmbH, Germany Drug: 1 capsule Prograf(R) (tacrolimus), Astellas Pharma GmbH, Germany Drug: 1 tablet Ezetrol(R) + 1 capsules Prograf(R) Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Pharmacokinetic Drug Interaction Between Ezetimibe and Tacrolimus After Single Dose Administration in Healthy Subjects

Resource links provided by NLM:


Further study details as provided by University Medicine Greifswald:

Primary Outcome Measures:
  • Primary characteristics: for ezetimibe: AUC0-∞, Cmax; for tacrolimus: AUC0-∞, Cmax [ Time Frame: September 2007 to November 2007 ]

Secondary Outcome Measures:
  • Second. characteristics: for ezetimibe: CLR, Ae (urine), Ae (feces); for ezetimibe glucuronide: AUC0-∞, Cmax, Ae (urine), Ae (feces); for ezetimibe, ezetimibe glucuronide and tacrolimus: AUC0-t, t½, tmax [ Time Frame: September 2007 to November 2007 ]

Enrollment: 24
Study Start Date: September 2007
Study Completion Date: November 2007
Primary Completion Date: November 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: C
administration of 1 tablet Ezetrol(R) (10 mg ezetimibe) and 1 capsule Prograf(R) (5 mg tacrolimus)
Drug: 1 tablet Ezetrol(R) + 1 capsules Prograf(R)
administration of 1 tablet Ezetrol(R) (10 mg ezetimibe) and 1 capsule Prograf(R) (5 mg Tacrolimus), 0-144 h blood sampling, 0-5 d urine sampling (24 h intervals) and 0-10 d feces sampling
Other Name: Ezetrol+Prograf
Active Comparator: A
administration of 1 tablet Ezetrol(R) (10 mg ezetimibe)
Drug: 1 tablet Ezetrol(R) (ezetimibe), MSD Sharp & Dohme GmbH, Germany
administration of 1 tablet Ezetrol(R) (10 mg ezetimibe), 0-144 h blood sampling, 0-5 d urine sampling (24 h intervals) and 0-10 d feces sampling
Other Name: Ezetrol
Active Comparator: B
administration of 1 capsule Prograf(R) (5 mg tacrolimus)
Drug: 1 capsule Prograf(R) (tacrolimus), Astellas Pharma GmbH, Germany
administration of 1 capsule Prograf(R) (5 mg tacrolimus), 0-144 h blood sampling
Other Name: Prograf

Detailed Description:
Hypercholesterolemia is a frequent finding in organ transplant recipients receiving immunosuppressive drugs such as tacrolimus. To prevent increased cardiovascular morbidity and mortality in these patients, co-medication with lipid-lowering statins is recommended. However, treatment with statins is limited in many patients by insufficient cholesterol-lowering efficacy, drug interactions and serious adverse drug reactions (e.g. rhabdomyolysis). These patients may benefit from comedication with the cholesterol absorption inhibitor ezetimibe. Since tacrolimus and ezetimibe were shown to be substrates of the efflux transporter ABCB1 (P-glycoprotein), drug interactions between both compounds may occur. Therefore, this clinical study in healthy subjects was initiated to evaluate the clinical relevance of drug/drug interactions between tacrolimus and ezetimibe according to the accepted bioequivalence approach.
  Eligibility

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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • age: 18 - 45 years
  • sex: male and female
  • ethnic origin: Caucasian
  • body weight: 19 kg/m² to 27 kg/m²
  • good health as evidenced by the results of the clinical examination, ECG, and the laboratory check-up, which are judged by the clinical investigator not to differ in a clinical relevant way from the normal state
  • written informed consent

Exclusion Criteria:

  • known allergy to macrolide antibiotics
  • existing cardiac or hematological diseases and/or pathological findings which might interfere with safety, pharmacodynamic effect and/or pharmacokinetics of ezetimibe and sirolimus
  • existing hepatic and renal diseases and/or pathological findings which might interfere with safety, pharmacodynamic effect and/or pharmacokinetics of ezetimibe and sirolimus
  • existing gastrointestinal diseases and/or pathological findings which might interfere with safety, pharmacodynamic effect and/or pharmacokinetics of ezetimibe and sirolimus
  • acute or chronic diseases which could affect drug absorption or metabolism
  • history of any serious psychological disorder
  • drug or alcohol dependence
  • positive drug or alcohol screening
  • smokers of 10 or more cigarettes per day
  • positive screening results for HIV, HBV and HCV
  • volunteers who are on a diet which could affect the pharmacokinetics of the drug
  • heavy tea or coffee drinkers (more than 1L per day)
  • lactation and pregnancy test positive or not performed
  • volunteers suspected or known not to follow instructions
  • volunteers who are unable to understand the written and verbal instructions, in particular regarding the risks and inconveniences they will be exposed to as a result of their participation in the study
  • volunteers liable to orthostatic dysregulation, fainting, or blackouts
  • blood donation or other blood loss of more than 400 ml within the last 12 weeks prior to the start of the study
  • participation in a clinical trial during the last 3 months prior to the start of the study
  • less than 14 days after last acute disease
  • any systemically available medication within 4 weeks prior to the intended first administration unless, because of the terminal elimination half-life, complete elimination from the body can be assumed for the drug and/or its primary metabolites (except oral contraceptives)
  • repeated use of drugs during the last 4 weeks prior to the intended first administration, which can influence hepatic biotransformation (e.g. barbiturates, cimetidine, phenytoin, rifampicin)
  • repeated use of drugs during the last 2 weeks prior to the intended first administration which affect absorption (e.g. laxatives, metoclopramide, loperamide, antacids, H2-receptor antagonists)
  • intake of grapefruit containing food or beverages within 7 days prior to administration
  • known allergic reactions to the active ingredients used or to constituents of the pharmaceutical preparation
  • subjects with severe allergies or multiple drug allergies
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00621699


Locations
Germany
Department of Clinical Pharmacology
Greifswald, Germany, 17487
Sponsors and Collaborators
University Medicine Greifswald
Investigators
Principal Investigator: Werner Siegmund, Prof Department of Clinical Pharmacology
  More Information

Responsible Party: Prof. Dr. W. Siegmund, MD, Department of Clinical Pharmacology
ClinicalTrials.gov Identifier: NCT00621699     History of Changes
Other Study ID Numbers: Eze-Tacro
2006-006549-14
First Submitted: February 12, 2008
First Posted: February 22, 2008
Last Update Posted: February 22, 2008
Last Verified: February 2008

Keywords provided by University Medicine Greifswald:
pharmacokinetics
drug interactions
ezetimibe
tacrolimus
human experimentation

Additional relevant MeSH terms:
Hypercholesterolemia
Hyperlipidemias
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Tacrolimus
Ezetimibe
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Lipid Regulating Agents