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

Pharmacokinetics Clinical Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00810303
• Other study ID #: Efavirenz - 2008
• Status: Completed
• Phase: Phase 1
• First received: December 17, 2008
• Last updated: September 23, 2010
• Start date: March 2009
• Est. completion date: July 2009

Study information

• Verified date: September 2010
• Source: University Medicine Greifswald
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: July 2009
• Est. primary completion date: July 2009
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 45 Years

Eligibility

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

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Drug Interactions
• Intestinal Transporter Expression
• Pharmacodynamics
• Pharmacokinetics

Intervention

Drug:
• Ezetrol (ezetimibe) multiple dose
administration of 1 tablet/day Ezetrol (10 mg ezetimibe) on study day 6-15 and a pharmakokinetic on study day 15 (0-24 h blood sampling, 0-24 h urine sampling and 5 d feces sampling (study day 11-15))
• Ezetrol (ezetimibe) multiple dose and Sustiva (efavirenz) single dose
administration of 1 tablet/day Ezetrol(R) (10 mg ezetimibe) on study day 16-20 and 2 capsules Sustiva(R) (2x200 mg efavirenz) on study day 16 with a pharmakokinetic (0-120 h blood sampling, urine sampling (24 h intervals) and feces sampling on study days 16-20)
• Ezetrol (ezetimibe) and Sustiva (efavirenz) multiple dose
administration of 1 tablet/day Ezetrol(R) (10 mg ezetimibe) and 2 capsules/day Sustiva(R) (2x200 mg efavirenz) on study day 21-30 and with a pharmakokinetic (0-120 h blood sampling, urine sampling (24 h intervals) on study day 30 and feces sampling on study day 26-30)
• Sustiva (efavirenz) single dose
administration of 2 capsules Sustiva(R) (2x200 mg efavirenz) on study day 1 with a pharmakokinetic (0-120 h blood sampling, urine sampling (24 h intervals) and feces sampling on study days 1-5)

Locations

Country	Name	City	State
Germany	Department of Clinical Pharmacology	Greifswald

Sponsors (1)

Lead Sponsor	Collaborator
University Medicine Greifswald

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	AUC0-24h of Free Ezetimibe (Steady-state Pharmacokinetic After Chronic Treatment With 10 mg Ezetimibe) on 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.	study day 15	No
Primary	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	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.	study day 16	No
Primary	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	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.	study day 30	No
Primary	Cmax of Free Ezetimibe (Steady-state Pharmacokinetic After Chronic Treatment With 10 mg Ezetimibe) on 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.	study day 15	No
Primary	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	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.	study day 16	No
Primary	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	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.	study day 30	No
Primary	AUC of Efavirenz (Single Dose Pharmacokinetic After Treatment With 400 mg Efavirenz) on 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.	study days 1-5	No
Primary	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	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.	study days 16-20	No
Primary	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	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.	study day 30	No
Primary	Cmax of Efavirenz (Single Dose Pharmacokinetic After Treatment With 400 mg Efavirenz) on 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.	study days 1-5	No
Primary	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	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.	study days 16-20	No
Primary	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	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.	study day 30	No
Secondary	AUC0-24h of Ezetimibe Glucuronide (Steady-state Pharmacokinetic After Chronic Treatment With 10 mg Ezetimibe) on 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.	study day 15	No
Secondary	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	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.	study day 16	No
Secondary	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	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.	study day 30	No
Secondary	Cmax of Ezetimibe Glucuronide (Steady-state Pharmacokinetic After Chronic Treatment With 10 mg Ezetimibe) on 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.	study day 15	No
Secondary	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	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.	study day 16	No
Secondary	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	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.	study day 30	No