Efavirenz, Metabolism and Pharmacokinetics Changes
Conditions
Keywords
Cytochrome P450, CYP2B6, Voriconazole, Efavirenz, Pharmacokinetics, Drug-Interactions, Pharmacogenetics, Healthy volunteers
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.
Interventions
DRUGEfavirenz
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.
DRUGvoriconazole
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.
Sponsors
National Institutes of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Indiana University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
SCREENING
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Measure Efavirenz Clearance | Baseline, 30 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 and 24h after efavirenz | Effect of steady-state voriconazole on efavirenz Clearance in healthy volunteers (n=61) administered a single 100 mg oral dose of efavirenz at baseline (control phase) and after treatment with voriconazole to steady-state. |
Countries
United States
Participant flow
Pre-assignment details
The study is started with Consent and screening (Laboratory and medical).Therefore 89 subjects gave consents and where screened. Of those 61 fully completed all phase of the study while 15 partially completed. The 13 subjects gave their consent and were screened, but they did not take any intervention because of abnormal labs.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 61 |
| Total | 61 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Consented but excluded after labs | 13 |
| Overall Study | Withdrawal by Subject | 15 |
Baseline characteristics
| Characteristic | CYP2B6 |
|---|---|
| Age, Continuous | 31.9 years STANDARD_DEVIATION 11.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 25 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 33 Participants |
| Region of Enrollment United States | 61 participants |
| Sex: Female, Male Female | 27 Participants |
| Sex: Female, Male Male | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 61 |
| serious Total, serious adverse events | 0 / 61 |
Outcome results
Primary
Measure Efavirenz Clearance
Effect of steady-state voriconazole on efavirenz Clearance in healthy volunteers (n=61) administered a single 100 mg oral dose of efavirenz at baseline (control phase) and after treatment with voriconazole to steady-state.
Time frame: Baseline, 30 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 and 24h after efavirenz
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CYP2B6 | Measure Efavirenz Clearance | Control | 45.51 ml/min/kg | Standard Deviation 18.3 |
| CYP2B6 | Measure Efavirenz Clearance | Vericonazole | 20.03 ml/min/kg | Standard Deviation 8.5 |