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

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to confirm a significant influence of ezetimibe and sirolimus on each others pharmacokinetics

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.

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

Conditions
-----------------
Pharmacokinetics, Drug Interactions, Hypercholesterolemia, Immunosuppression

Intervention / Treatment
-----------------
* 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)


Participation Criteria
=================
Eligibility 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: A<br>administration of 1 tablet Ezetrol(R) (10 mg ezetimibe) | Drug: 1 tablet Ezetrol(R) (ezetimibe), MSD Sharp & Dohme GmbH, Germany<br>* 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<br>* Other names: Ezetrol;|
| Active Comparator: B<br>administration of 5 ml Rapamune(R) oral solution (1 mg/ml sirolimus) | Drug: 1 tablet Rapamune(R) (sirolimus), Wyeth Pharma, Germany<br>* administration of 5 ml Rapamune(R) oral solution (1 mg/ml sirolimus), 0-144 h blood sampling<br>* Other names: Rapamune;|
| Experimental: C<br>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)<br>* 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<br>* Other names: Ezetrol+Rapamune;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary characteristics: for ezetimibe: AUC0-∞, Cmax; for sirolimus: AUC0-∞, Cmax |  | April 2007 to June 2007 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
pharmacokinetics, drug interactions, ezetimibe, sirolimus, human experimentation