Determine the Effects of Gene Differences and Voriconazole on Enzyme CYP2B6 Activity in the Liver in Healthy Volunteers

NCT ID: NCT01104376

Last Updated: 2014-12-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 61 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-03-31
• Study Completion Date: 2013-04-30

Brief Summary

The purpose of this study is to see if administration of medicines and genetic differences affects the activity of a liver enzyme called CYP2B6 in healthy volunteers.

Detailed Description

The investigators will test the hypothesis that CYP2B6 genetic variants that show effects in vitro also influence the in vivo activity of CYP2B6 and its responsiveness to metabolic inhibition, using the metabolism of efavirenz (100 mg dose) as a marker of activity. The metabolism and pharmacokinetics of efavirenz will be determined in a total of 60 healthy volunteers with CYP2B6*1/*1, CYP2B6*1*6 and CYP2B6*6*6 at baseline (control) and after pretreatment with voriconazole.

Conditions

Efavirenz, Metabolism and Pharmacokinetics Changes

Keywords

Cytochrome P450; CYP2B6; Voriconazole; Efavirenz; Pharmacokinetics; Drug-Interactions; Pharmacogenetics; Healthy volunteers

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: SCREENING
• Blinding Strategy: NONE

Study Groups

CYP2B6

Healthy volunteers will receive Efavirenz and Vericonazole as follow:

In phase 1 day 1 (control phase) a single 100mg dose of efavirenz will be administered. In phase 2 (voriconazole pretreatment phase), the subject will be pretreated with voriconazole (400mg twice daily on phase 2 day 8 and then 200mg twice daily for the next consecutive 8 days. In phase 3 (efavirenz plus voriconazole phase), the subject will receive on phase 3 day 10 100mg single dose of efavirenz along with 200mg of voriconazole twice daily.

Group Type: EXPERIMENTAL

Efavirenz

Intervention Type: DRUG

In phase 1 day 1 (control phase) a single 100mg dose of efavirenz will be administered.

In phase 2 (voriconazole pretreatment phase), the subject will be pretreated with voriconazole (400mg twice daily on phase 2 day 8 and then 200mg twice daily for the next consecutive 8 days. In phase 3 (efavirenz plus voriconazole phase), the subject will receive on phase 3 day 10 100mg single dose of efavirenz along with 200mg of voriconazole twice daily.

voriconazole

Intervention Type: DRUG

In phase 1 day 1 (control phase) a single 100mg dose of efavirenz will be administered.

In phase 2 (voriconazole pretreatment phase), the subject will be pretreated with voriconazole (400mg twice daily on phase 2 day 8 and then 200mg twice daily for the next consecutive 8 days. In phase 3 (efavirenz plus voriconazole phase), the subject will receive on phase 3 day 10 100mg single dose of efavirenz along with 200mg of voriconazole twice daily.

Interventions

Efavirenz

In phase 1 day 1 (control phase) a single 100mg dose of efavirenz will be administered.

In phase 2 (voriconazole pretreatment phase), the subject will be pretreated with voriconazole (400mg twice daily on phase 2 day 8 and then 200mg twice daily for the next consecutive 8 days. In phase 3 (efavirenz plus voriconazole phase), the subject will receive on phase 3 day 10 100mg single dose of efavirenz along with 200mg of voriconazole twice daily.

Intervention Type: DRUG

voriconazole

In phase 1 day 1 (control phase) a single 100mg dose of efavirenz will be administered.

In phase 2 (voriconazole pretreatment phase), the subject will be pretreated with voriconazole (400mg twice daily on phase 2 day 8 and then 200mg twice daily for the next consecutive 8 days. In phase 3 (efavirenz plus voriconazole phase), the subject will receive on phase 3 day 10 100mg single dose of efavirenz along with 200mg of voriconazole twice daily.

Intervention Type: DRUG

Other Intervention Names

Sustiva; Vfend

Eligibility Criteria

Inclusion Criteria

• Male or female subject between 18 and 55 years of age.
• Healthy individuals without any significant medical conditions as determined by a screening performed at University.
• Adherence to the study dietary and medication restrictions.
• Willingness to refrain from smoking or use of tobacco or marijuana one week before the start of the study and until completion of the study which will be a total of 17 days.
• Ability to commit the time requested for this study.

Exclusion Criteria

• Underweight (weighs less than 50kg or 110lb) or over weight [body mass index (BMI) greater than 32].
• Drug or alcohol abuse (more than 3 alcoholic drinks per day on a regular basis).
• History of intolerance or allergic reaction (e.g. rash) to efavirenz and/or voriconazole.
• Significant health conditions such heart, gastrointestinal disorders, liver, or kidney diseases that may be exacerbated during the course of the study.
• History or current psychiatric illness (e.g. depression, anxiety, or nervousness).
• History or current eye sight disturbances (e.g. blurred vision).
• Serious infection within the last 2 weeks.
• Blood donation within the past two months.
• Screening results that do not fall in a healthy range.
• Regularly taking prescriptions (except hormonal agents, e.g. oral contraceptives), over-the-counter, herbal or dietary supplements, and alternative medications and are unable or unwilling to stop taking them one week before and during the study periods.
• Female with a positive pregnancy test.
• Female breastfeeding.
• Females of child-bearing potential who are unable or unwilling to either practice abstinence or use appropriate birth control up until the study completion, which will take a total of 17 days.
• Participation in a research study involving intensive blood sampling and/or have use study drugs in the last two months.
• Employed or student under supervision of any of the investigators of this study.
• Inability to state a good understanding of this study including risks and requirements, and inability to follow the rules of this study.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

National Institute of General Medical Sciences (NIGMS)

NIH

Sponsor Role: collaborator

Indiana University

OTHER

Sponsor Role: lead

Responsible Party

Zeruesenay Desta

Associate Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Zeruesenay Desta, PhD

Role: PRINCIPAL_INVESTIGATOR

IU Department of Medicine/Division of Clinical Pharmacology

Locations

Indiana University

Indianapolis, Indiana, United States

Countries

United States

References

Desta Z, Metzger IF, Thong N, Lu JB, Callaghan JT, Skaar TC, Flockhart DA, Galinsky RE. Inhibition of Cytochrome P450 2B6 Activity by Voriconazole Profiled Using Efavirenz Disposition in Healthy Volunteers. Antimicrob Agents Chemother. 2016 Oct 21;60(11):6813-6822. doi: 10.1128/AAC.01000-16. Print 2016 Nov.

Reference Type: DERIVED

PMID: 27600044 (View on PubMed)

Other Identifiers

R01GM078501

Identifier Type: NIH

Identifier Source: secondary_id

View Link

0808-16

Identifier Type: -

Identifier Source: org_study_id