Pharmacokinetic and Pharmacodynamic Interactions Between the Cholesterol-lowering Ezetimibe and the Non-nucleoside Reverse Transcriptase Inhibitor Efavirenz During Chronic Treatment in Healthy Volunteers With Reference to Intestinal Expression of CYP3A4, UGT1A1, ABCB1 and ABCC2

Phase 1

Completed

Conditions: Pharmacokinetics
Drug Interactions
Pharmacodynamics
Intestinal Transporter Expression

Interventions: Drug: Ezetrol (ezetimibe) multiple dose
Drug: Ezetrol (ezetimibe) multiple dose and Sustiva (efavirenz) single dose
Drug: Ezetrol (ezetimibe) and Sustiva (efavirenz) multiple dose
Drug: Sustiva (efavirenz) single dose

Registration Number: NCT00810303

Lead Sponsor: University Medicine Greifswald

Brief Summary: The purpose of this study is to evaluate the effects of a chronic co-medication of efavirenz on pharmacokinetics and sterol-lowering effects of ezetimibe at steady-state in healthy subjects genotyped for ABCB1, ABCC2, CYP2B6 and UGT1A1.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 12

Inclusion Criteria

age: 18 - 45 years
sex: male and female
ethnic origin: Caucasian
body weight: 19 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

existing cardiac or haematological diseases and/or pathological findings, which might interfere with the drug's safety, tolerability, absorption and/or pharmacokinetics
existing hepatic and renal diseases and/or pathological findings, which might interfere with the drug's safety, tolerability, absorption and/or pharmacokinetics
existing gastrointestinal diseases and/or pathological findings, which might interfere with the drug's safety, tolerability, absorption and/or pharmacokinetics
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 anti-HIV-test, HBs-Ag-test or anti-HCV-test
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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
whole study group	Ezetrol (ezetimibe) and Sustiva (efavirenz) multiple dose	A study with a duration of 34 days with 4 periods (= 4 pharmakokinetics) on 12 healthy subjects.
whole study group	Ezetrol (ezetimibe) multiple dose	A study with a duration of 34 days with 4 periods (= 4 pharmakokinetics) on 12 healthy subjects.
whole study group	Ezetrol (ezetimibe) multiple dose and Sustiva (efavirenz) single dose	A study with a duration of 34 days with 4 periods (= 4 pharmakokinetics) on 12 healthy subjects.
whole study group	Sustiva (efavirenz) single dose	A study with a duration of 34 days with 4 periods (= 4 pharmakokinetics) on 12 healthy subjects.

Primary Outcome Measures

Name	Time	Method
AUC0-24h of Free Ezetimibe (Steady-state Pharmacokinetic After Chronic Treatment With 10 mg Ezetimibe) on Study Day 15	study day 15	The area under the concentrations-time curve (AUC0-24) was calculated with the measured data points from the time of administration up to 24 h after administration by the trapezoidal formula. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free ezetimibe in the blood samplings.
AUC0-24h of Free Ezetimibe (Steady-state Pharmacokinetic After Chronic Treatment With 10 mg Ezetimibe and Concomitant Chronic Treatment With 400 mg Efavirenz) on Study Day 30	study day 30	The area under the concentrations-time curve (AUC0-24) was calculated with the measured data points from the time of administration up to 24 h after administration by the trapezoidal formula. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free ezetimibe in the blood samplings.
Cmax of Free Ezetimibe (Steady-state Pharmacokinetic After Chronic Treatment With 10 mg Ezetimibe and Concomitant Single Dose Administration of 400 mg Efavirenz) on Study Day 16	study day 16	The maximum concentration (Cmax) were obtained directly from the measured concentration-time curves. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free ezetimibe in the blood samplings.
Cmax of Free Ezetimibe (Steady-state Pharmacokinetic After Chronic Treatment With 10 mg Ezetimibe and Concomitant Chronic Treatment With 400 mg Efavirenz) on Study Day 30	study day 30	The maximum concentration (Cmax) were obtained directly from the measured concentration-time curves. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free ezetimibe in the blood samplings.
AUC of Efavirenz (Single Dose Pharmacokinetic After Treatment With 400 mg Efavirenz) on Study Days 1-5	study days 1-5	The area under the concentrations-time curve (AUC) was calculated with the measured data points from the time of administration until the last quantificable concentration by the trapezoidal formula and the extrapolation to infinity. The concentration-time curve is the result of time points of blood sampling and its measured concentration of efavirenz in the blood samplings.
Cmax of Efavirenz (Steady State Pharmacokinetic After Chronic Treatment With 400 mg Efavirenz and Concomitant Chronic Treatment of 10 mg Ezetimibe) on Study Day 30	study day 30	The maximum concentration (Cmax) were obtained directly from the measured concentration-time curves. The concentration-time curve is the result of time points of blood sampling and its measured concentration of efavirenz in the blood samplings.
AUC0-24h of Free Ezetimibe (Steady-state Pharmacokinetic After Chronic Treatment With 10 mg Ezetimibe and Concomitant Single Dose Administration of 400 mg Efavirenz) on Study Day 16	study day 16	The area under the concentrations-time curve (AUC0-24) was calculated with the measured data points from the time of administration up to 24 h after administration by the trapezoidal formula. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free ezetimibe in the blood samplings.
AUC of Efavirenz (Single Dose Pharmacokinetic After Treatment With 400 mg Efavirenz and Concomitant Chronic Treatment of 10 mg Ezetimibe) on Study Days 16-20	study days 16-20	The area under the concentrations-time curve (AUC) was calculated with the measured data points from the time of administration until the last quantificable concentration by the trapezoidal formula and the extrapolation to infinity. The concentration-time curve is the result of time points of blood sampling and its measured concentration of efavirenz in the blood samplings.
AUC0-24h of Efavirenz (Steady State Pharmacokinetic After Chronic Treatment With 400 mg Efavirenz and Concomitant Chronic Treatment of 10 mg Ezetimibe) on Study Day 30	study day 30	The area under the concentrations-time curve (AUC0-24) was calculated with the measured data points from the time of administration up to 24 h after administration by the trapezoidal formula. The concentration-time curve is the result of time points of blood sampling and its measured concentration of efavirenz in the blood samplings.
Cmax of Efavirenz (Single Dose Pharmacokinetic After Treatment With 400 mg Efavirenz) on Study Days 1-5	study days 1-5	The maximum concentration (Cmax) were obtained directly from the measured concentration-time curves. The concentration-time curve is the result of time points of blood sampling and its measured concentration of efavirenz in the blood samplings.
Cmax of Efavirenz (Single Dose Pharmacokinetic After Treatment With 400 mg Efavirenz and Concomitant Chronic Treatment of 10 mg Ezetimibe) on Study Days 16-20	study days 16-20	The maximum concentration (Cmax) were obtained directly from the measured concentration-time curves. The concentration-time curve is the result of time points of blood sampling and its measured concentration of efavirenz in the blood samplings.
Cmax of Free Ezetimibe (Steady-state Pharmacokinetic After Chronic Treatment With 10 mg Ezetimibe) on Study Day 15	study day 15	The maximum concentration (Cmax) were obtained directly from the measured concentration-time curves. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free ezetimibe in the blood samplings.

Secondary Outcome Measures

Name	Time	Method
Cmax of Ezetimibe Glucuronide (Steady-state Pharmacokinetic After Chronic Treatment With 10 mg Ezetimibe) on Study Day 15	study day 15	The maximum concentration (Cmax) were obtained directly from the measured concentration-time curves. The concentration-time curve is the result of time points of blood sampling and its measured concentration of ezetimibe glucuronide in the blood samplings.
Cmax of Ezetimibe Glucuronide (Steady-state Pharmacokinetic After Chronic Treatment With 10 mg Ezetimibe and Concomitant Single Dose Administration of 400 mg Efavirenz) on Study Day 16	study day 16	The maximum concentration (Cmax) were obtained directly from the measured concentration-time curves. The concentration-time curve is the result of time points of blood sampling and its measured concentration of ezetimibe glucuronide in the blood samplings.
Cmax of Ezetimibe Glucuronide (Steady-state Pharmacokinetic After Chronic Treatment With 10 mg Ezetimibe and Concomitant Chronic Treatment With 400 mg Efavirenz) on Study Day 30	study day 30	The maximum concentration (Cmax) were obtained directly from the measured concentration-time curves. The concentration-time curve is the result of time points of blood sampling and its measured concentration of ezetimibe glucuronide in the blood samplings.
AUC0-24h of Ezetimibe Glucuronide (Steady-state Pharmacokinetic After Chronic Treatment With 10 mg Ezetimibe) on Study Day 15	study day 15	The area under the concentrations-time curve (AUC0-24) was calculated with the measured data points from the time of administration up to 24 h after administration by the trapezoidal formula. The concentration-time curve is the result of time points of blood sampling and its measured concentration of ezetimibe glucuronide in the blood samplings.
AUC0-24h of Ezetimibe Glucuronide (Steady-state Pharmacokinetic After Chronic Treatment With 10 mg Ezetimibe and Concomitant Single Dose Administration of 400 mg Efavirenz) on Study Day 16	study day 16	The area under the concentrations-time curve (AUC0-24) was calculated with the measured data points from the time of administration up to 24 h after administration by the trapezoidal formula. The concentration-time curve is the result of time points of blood sampling and its measured concentration of ezetimibe glucuronide in the blood samplings.
AUC0-24h of Ezetimibe Glucuronide (Steady-state Pharmacokinetic After Chronic Treatment With 10 mg Ezetimibe and Concomitant Chronic Treatment With 400 mg Efavirenz) on Study Day 30	study day 30	The area under the concentrations-time curve (AUC0-24) was calculated with the measured data points from the time of administration up to 24 h after administration by the trapezoidal formula. The concentration-time curve is the result of time points of blood sampling and its measured concentration of ezetimibe glucuronide in the blood samplings.