CYP2B6 Genetics and Drug Interactions in Healthy Volunteers

Overview

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.

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.