CYP2B6 Genetics and Drug Interactions in Healthy Volunteers

• Status: Completed
• Trial end date: 2016-05-31
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 4
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Indiana University
• Collaborator: National Institute of General Medical Sciences (NIGMS)
• Treatments: Bupropion; Efavirenz; Montelukast; Rosuvastatin Calcium

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