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
Condition: Pharmacokinetics; Drug Interactions; Pharmacodynamics; Intestinal Transporter Expression
Intervention: Ezetrol (ezetimibe) multiple dose; Ezetrol (ezetimibe) multiple dose and Sustiva (efavirenz) single dose; Ezetrol (ezetimibe) and Sustiva (efavirenz) multiple dose; Sustiva (efavirenz) single dose
Intervention description: 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)); 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); 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); 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)
Intervention MeSH terms: Efavirenz; Ezetimibe
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 12.0
Sex: All
Minimum age: 18 Years
Maximum age: 45 Years
Healthy volunteers: Accepts Healthy Volunteers

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.
    

Eligibility criteria:

        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