CYP2B6 Genetics and Drug Interactions in Healthy Volunteers
Condition: Healthy
Intervention: Efavirenz; Bupropion; Rosuvastatin; Montelukast
Intervention description: The study has 4 phases:
Phase 1 (control)-Subjects will receive simultaneously a single dose of bupropion 100 mg, montelukast 10 mg and rosuvastatin 5 mg (cocktail) by mouth (control).
Phase 2 (inhibition)- a single 600 mg oral dose of efavirenz (blood draw at 30 min and 1 hour) will be administered with the cocktail drugs.
Phase 3 (home treatment with efavirenz): Subjects will take efavirenz at home (600 mg/day for 17 days).
Phase 4 (Induction) - is the same as phase 2. Blood samples (0 to 120 hrs) and urine voided over 48 hrs (Phases 1, 2 and 4) are collected. Blood draws will be made in phase 3 for trough concentration measurements.; The study has 4 phases:
Phase 1 (control)-Subjects will receive simultaneously a single dose of bupropion 100 mg, montelukast 10 mg and rosuvastatin 5 mg (cocktail) by mouth (control).
Phase 2 (inhibition)- a single 600 mg oral dose of efavirenz (blood draw at 30 min and 1 hour) will be administered with the cocktail drugs.
Phase 3 (home treatment with efavirenz): Subjects will take efavirenz at home (600 mg/day for 17 days).
Phase 4 (Induction) - is the same as phase 2. Blood samples (0 to 120 hrs) and urine voided over 48 hrs (Phases 1, 2 and 4) are collected. Blood draws will be made in phase 3 for trough concentration measurements.; The study has 4 phases:
Phase 1 (control)-Subjects will receive simultaneously a single dose of bupropion 100 mg, montelukast 10 mg and rosuvastatin 5 mg (cocktail) by mouth (control).
Phase 2 (inhibition)- a single 600 mg oral dose of efavirenz (blood draw at 30 min and 1 hour) will be administered with the cocktail drugs.
Phase 3 (home treatment with efavirenz): Subjects will take efavirenz at home (600 mg/day for 17 days).
Phase 4 (Induction) - is the same as phase 2. Blood samples (0 to 120 hrs) and urine voided over 48 hrs (Phases 1, 2 and 4) are collected. Blood draws will be made in phase 3 for trough concentration measurements.; The study has 4 phases:
Phase 1 (control)-Subjects will receive simultaneously a single dose of bupropion 100 mg, montelukast 10 mg and rosuvastatin 5 mg (cocktail) by mouth (control).
Phase 2 (inhibition)- a single 600 mg oral dose of efavirenz (blood draw at 30 min and 1 hour) will be administered with the cocktail drugs.
Phase 3 (home treatment with efavirenz): Subjects will take efavirenz at home (600 mg/day for 17 days).
Phase 4 (Induction) - is the same as phase 2. Blood samples (0 to 120 hrs) and urine voided over 48 hrs (Phases 1, 2 and 4) are collected. Blood draws will be made in phase 3 for trough concentration measurements.
Intervention MeSH terms: Efavirenz; Bupropion; Rosuvastatin Calcium; Montelukast
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 70.0
Sex: All
Minimum age: 18 Years
Maximum age: 49 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Efavirenz; metabolism; pharmacokinetics changes

Summary:

      The CYP2B6 enzyme metabolizes a growing number of clinically important drugs such as the
      anti-HIV drug efavirenz, but its activity in the liver is highly variable, which may lead to
      failure of therapy or toxicity and unpredictable drug interactions. Genetic and several
      nongenetic factors affect the activity of CYP2B6. The goal of this study is to determine the
      impact of simultaneous autoinhibition/autoinduction and CYP2B6 genetics on CYP2B6 activity,
      efavirenz exposure and efavirenz-mediated drug interactions. The pharmacokinetics and drug
      interactions will be determined on three occasions in a total of 60 healthy volunteers. The
      whole study will have 4 phases. A) Phase 1 (baseline control): using selective probe
      substrates, the baseline activities of CYP2B6 (bupropion), CYP2C8 (montelukast) and OATP1B1
      (rosuvastatin) are determined. B) Phase 2 (inhibition): the metabolism and pharmacokinetics
      of a single 600 mg oral dose of efavirenz) and the activities of CYP2B6, CYP2C8 and OATP1B1
      (inhibition) are determined. C) Phase 3 (treatment phase): After completing phase 2, subjects
      take 600 mg/day efavirenz at home for 17 days. C) Phase 4 (induction and inhibition): At the
      end of phase 3, steady state metabolism and pharmacokinetics of efavirenz and the activities
      of CYP2B6, CYP2C8 and OATP1B1 will be determined. Efavirenz serves as a model substrate,
      inhibitor and inducer of CYP2B6 (and other drug disposition proteins). Bupropion
      4-hydroxylation is an alternative in vivo probe of CYP2B6 activity and will be studied here
      in addition to the metabolism and pharmacokinetics of efavirenz.
    

Eligibility criteria:

        A total of 60 healthy female and male volunteers (18 to 49 years old) who meet all
        inclusion and exclusion criterion listed below will be enrolled to participate in this
        study. All subjects will sign an Institutional Review Board (IRB) approved written informed
        consent prior to participation in the study after subjects read and carefully explained of
        the study to them. Then, potential subjects will undergo a pre-enrollment screening
        examination (a maximum of six weeks prior to enrollment into the study) for any medical
        abnormalities which will include medical histories, vital signs and electrocardiography,
        demographic variables, and standard laboratory blood and urine tests. The screening will be
        performed at the Indiana Clinical Research Center. During the screening, a blood sample (15
        ml) will be collected from each subject for laboratory tests and urine for urine analyses.
        An additional ∼10 ml will be obtained from each subject to extract genomic DNA for
        genotyping purposes.

        INCLUSION CRITERIA:

          -  18 to 49 years old healthy male and female participants within 32% of their ideal body
             weight

          -  Individuals who agree to refrain from taking any prescriptions medications,
             over-the-counter medications, hormonal agents, and herbal, dietary, and alternative
             supplements that may interact with the metabolism of those study drugs at least 2
             weeks prior to the start of the study and until study completion

          -  Nonsmoker or individuals willing to refrain from smoking or use of tobacco or
             marijuana for at least one month prior to and until the completion of the study (the
             entire study lasts for approximately 38 days)

        EXCLUSION CRITERIA:

          -  Are underweight (less than 114 lb) or overweight (BMI greater than 32)

          -  Have history or current alcohol or drug abuse (more than 4 alcoholic drinks per day on
             a regular basis)

          -  Have history of intolerance, allergic reactions (e.g. rash) or other forms of
             hypersensitivities to any of the study medications (efavirenz, montelukast, bupropion
             and rosuvastatin)

          -  Have history or current significant health conditions such as heart, liver, or kidney

          -  Have history or current psychiatric illness such as depression, anxiety, or
             nervousness that may be exacerbated by participation in study

          -  Have a history of suicidality including suicide attempts

          -  Have history or current gastrointestinal disorders such as persistent diarrhea or
             malabsorption that would interfere with the absorption of orally administered drugs

          -  Have a serious infection within the last week before study enrollment

          -  Have a baseline EKG readings that is abnormal that could place the patient at the
             higher risk as decided by the study medical doctor (MD)

          -  Have donated blood within the past two months

          -  Have blood results that do not fall in a healthy range

          -  Are taking on regular basis substances that may interfere with the metabolism of study
             medications by the body, including prescription medications, over-the-counter, herbal
             or dietary supplements, alternative medications, or hormonal agents

          -  Are female with a positive pregnancy urine test obtained just prior to each study

          -  Are female breastfeeding

          -  Are child-bearing potential unable or unwilling to either practice abstinence or use
             two non-hormonal forms of birth control up until the study completion, which will take
             a total of 38 days

          -  Have a life style that places subjects at a higher risk for contracting HIV (e.g. drug
             abuse, excessive alcohol drinking, and having multiple sexual partners)

          -  Have a history or current HIV infection

          -  Have participation in a research study or use of an investigational drug in the last
             one month

          -  Are employed or are student under supervision of any of the investigators of this
             study

          -  Cannot state a good understanding of this study including risks and requirements; are
             unable to follow the rules of this study

          -  Cannot commit the time requested for this study