CYP2B6 Genetics and Drug Interactions in Healthy Volunteers
Condition: Healthy
Study type: Interventional
Phase: Phase 4

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.
    

Detailed description: 
      Schedule of assessment

      PHASE 1 (CONTROL PHASE)

      Phase 1 (day 1 to day 4): baseline (control) activities of CYP2B6, CYP2C8 and OATP1B1 will be
      measured using selective probe substrates. Eligible subjects will receive simultaneously a
      single 100 mg dose of bupropion (CYP2B6), a single 10 mg dose montelukast (CYP2C8) and a
      single 5 mg dose of rosuvastatin (OATP1B1) by mouth on empty stomach together at least 10
      days before phase 2. Frequent plasma samples will be collected for 72 hours and urine for 48
      hours after dosing. Safety assessment will be made for the first 24 hours. Phase 1 is
      completed after the last blood draw on day 4 (72 hours).

      PHASE 2 (INHIBITION PHASE)

      In phase 2 (days 11 to 16), the metabolism and pharmacokinetics of a single 600 mg oral dose
      efavirenz will be determined along with the activities of CYP2B6, CYP2C8 and OATP1B1.
      Subjects receive a single 600 mg oral dose of efavirenz and blood samples will be obtained at
      30 min and 1 hour. Immediately after the 1 hour blood draw, the three probe drugs (10 mg
      montelukast, 100 mg bupropion, and 5 mg rosuvastatin) will be administered simultaneously.
      Frequent plasma samples will be collected for 120 hours and urine for 48 hours after
      efavirenz dosing. Safety assessment will be made for the first 24 hours. Phase 2 is completed
      after the last blood draw on day 16 (120 hours). Note: The additional time points (compared
      to phase 1) are needed because of the long elimination half-life of efavirenz.

      PHASE 3 (EFAVIRENZ TREATMENT PHASE).

      In phase 3 (days 16 to 32), subjects will take efavirenz (600 mg/day) every evening for 17
      days (Note: Phase 3 starts when the subject takes the first dose that evening on Day 16).
      Prior to taking the evening dose, they will be requested to return to the Indiana Clinical
      Research Center on day 19, day 22, day 25, day 28 and day 31 for a brief outpatient visit to
      have vital signs checked, draw blood sample (~10 ml, approximately 2 teaspoonful), and to
      fill out the brief central nervous system (CNS) symptoms questionnaire. They will be reminded
      not to take the evening dose of efavirenz on these days until after their blood draw. Since
      efavirenz has a long half-life (~76 hours after single dose and ~50 at steady state), a total
      of 17 days of efavirenz treatment is required to achieve steady-state plasma concentrations
      of efavirenz and steady-state autoinduction of metabolism. Subjects will be instructed to
      take efavirenz at bed-time to minimize efavirenz-induced central nervous side effects. Minor
      rescheduling (±3 days) of the subject's fixed inpatient/outpatient visits will be allowed
      including adjusting the amount of study medication (up to 3 doses less or up to 3 doses more)
      to be given prior to the subject's 4th inpatient visit.

      PHASE 4 (INHIBITION/INDUCTION PHASE)

      In phase 4 (days 33 to 38), the steady-state metabolism and pharmacokinetics of efavirenz
      will be determined along the activities of CYP2B6, CYP2C8 and OATP1B1. The procedures
      described in phase 2 will be repeated. On day 38, an exit exam will be performed consisting
      of a repeat of a repeat of the screening laboratory tests including blood and urine tests.
      The study diary will be collected. Medication bottles with left over pills (if any) will be
      returned and pills remaining will be counted for compliance purposes. The total duration of
      the study will be 38 days.
    

Intervention name(s): Efavirenz; Bupropion; Rosuvastatin; Montelukast
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): 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.
Other intervention name(s): Sustiva; Wellbutrin; Crestor; Singulair
Intervention MeSH terms: Efavirenz; Bupropion; Rosuvastatin Calcium; Montelukast
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Efavirenz; metabolism; pharmacokinetics changes