CYP2B6 Genetics and Drug Interactions in Healthy Volunteers

NCT02401256 | Completed Phase 4 Results DMC

• 2 other identifiers: 12050087395R01GM078501
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Healthy

Keywords

Efavirenz; metabolism; pharmacokinetics changes

Outcome Measures

Primary Outcomes (1)

• Efavirenz AUC0-inf (Single Dose) and AUC0-24(Multiple Dose)

  After the samples collection, blood from phase 2 and phase 4 were used to perform the quantification of Efavirenz in plasma. The composite of the efavirenz concentration (blood collection between 0 to 120 hrs) were used to calculate the area under the plasma concentration time curve (AUC0-inf for single dose and AUC0-24 for multiple dose) of efavirenz.

  Single dose pharmacokinetics (PK) versus multiple doses (after 17 day pretreatment) PK (total 38 days for each subject)

Study Arms (1)

CYP2B6

EXPERIMENTAL

This is a fixed-order, open label prospective cohort study to determine: a) the contribution of CYP2B6 autoinhibition/autoinduction processes to variable CYP2B6 activity and efavirenz exposure; b) the impact of CYP2B6 genetic variants on these processes; and c) drug interactions that ensue. Included drugs: Efavirenz (600mg) - The volunteers will receive it in two of three inpatient visits and also during 17 days at home Bupropion (100mg), Montelukast (10mg) and Rosuvastatin (5mg) - These drugs will be administrated on 3 occasions (at the begging each inpatient visit of Phase 1, 2 and 4).

Drug: Efavirenz; Drug: Bupropion; Drug: Rosuvastatin; Drug: Montelukast

Interventions

Efavirenz DRUG

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.

Also known as: Sustiva

CYP2B6

Bupropion DRUG

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.

Also known as: Wellbutrin

CYP2B6

Rosuvastatin DRUG

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.

Also known as: Crestor

CYP2B6

Montelukast DRUG

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.

Also known as: Singulair

CYP2B6

Eligibility Criteria

• Age: 18 Years - 49 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Indiana University: lead
• National Institute of General Medical Sciences (NIGMS): collaborator

Study Sites (1)

Indiana University School of Medicine

Indianapolis, Indiana, 46202, United States

Location

MeSH Terms

Interventions

efavirenz; Bupropion; Rosuvastatin Calcium; montelukast

Intervention Hierarchy (Ancestors)

Propiophenones; Ketones; Organic Chemicals; Sulfonamides; Amides; Fluorobenzenes; Hydrocarbons, Fluorinated; Hydrocarbons, Halogenated; Hydrocarbons; Sulfones; Sulfur Compounds; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Zeruesenay Desta
• Organization: Indiana University School of Medicine

zdesta@iu.edu

3172742823

Study Officials

• Zeruesenay Desta, PhD

  +1 (317) 274-2823

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Research Professor

Study Record Dates

• First Submitted: February 26, 2015
• First Posted: March 27, 2015
• Study Start: July 1, 2013
• Primary Completion: May 1, 2016
• Study Completion: May 31, 2016
• Last Updated: October 11, 2017
• Results First Posted: October 11, 2017

Record last verified: 2017-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)