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

Sponsor

University Medicine Greifswald (Other)

Overall Status

Completed

CT.gov ID

NCT00621101

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to confirm a significant influence of ezetimibe and sirolimus on each others pharmacokinetics

Condition or Disease	Intervention/Treatment	Phase
Pharmacokinetics Drug Interactions Hypercholesterolemia Immunosuppression	Drug: 1 tablet Ezetrol(R) (ezetimibe), MSD Sharp & Dohme GmbH, Germany Drug: 1 tablet Rapamune(R) (sirolimus), Wyeth Pharma, Germany Drug: 1 tablet Ezetrol(R) + 1 tablet Rapamune(R)	Phase 1

Detailed Description

Hypercholesterolemia is a frequent finding in organ transplant recipients receiving immunosuppressive drugs such as sirolimus. 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 (EZE). Since SIR and EZE 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 sirolimus and ezetimibe according to the accepted bioequivalence approach.

Study Design

Study Type:

Interventional

Actual Enrollment :

24 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

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

Study Start Date :

Apr 1, 2007

Actual Primary Completion Date :

Jun 1, 2007

Actual Study Completion Date :

Jun 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
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 Names: Ezetrol
Active Comparator: B administration of 5 ml Rapamune(R) oral solution (1 mg/ml sirolimus)	Drug: 1 tablet Rapamune(R) (sirolimus), Wyeth Pharma, Germany administration of 5 ml Rapamune(R) oral solution (1 mg/ml sirolimus), 0-144 h blood sampling Other Names: Rapamune
Experimental: C administration of 1 tablet Ezetrol(R) (10 mg ezetimibe) and 5 ml Rapamune(R) oral solution (1 mg/ml sirolimus)	Drug: 1 tablet Ezetrol(R) + 1 tablet Rapamune(R) administration of 1 tablet Ezetrol(R) (10 mg ezetimibe) and 5 ml Rapamune(R) oral solution (1 mg/ml sirolimus), 0-144 h blood sampling, 0-5 d urine sampling (24 h intervals) and 0-10 d feces sampling Other Names: Ezetrol+Rapamune

Arm

Intervention/Treatment

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 Names:

Ezetrol

Active Comparator: B

administration of 5 ml Rapamune(R) oral solution (1 mg/ml sirolimus)

Drug: 1 tablet Rapamune(R) (sirolimus), Wyeth Pharma, Germany

administration of 5 ml Rapamune(R) oral solution (1 mg/ml sirolimus), 0-144 h blood sampling

Other Names:

Rapamune

Experimental: C

administration of 1 tablet Ezetrol(R) (10 mg ezetimibe) and 5 ml Rapamune(R) oral solution (1 mg/ml sirolimus)

Drug: 1 tablet Ezetrol(R) + 1 tablet Rapamune(R)

administration of 1 tablet Ezetrol(R) (10 mg ezetimibe) and 5 ml Rapamune(R) oral solution (1 mg/ml sirolimus), 0-144 h blood sampling, 0-5 d urine sampling (24 h intervals) and 0-10 d feces sampling

Other Names:

Ezetrol+Rapamune

Outcome Measures

Primary Outcome Measures

Primary characteristics: for ezetimibe: AUC0-∞, Cmax; for sirolimus: AUC0-∞, Cmax [April 2007 to June 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 sirolimus: AUC0-t, t½, tmax [April 2007 to June 2007]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 45 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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