Healthy
Conditions
Keywords
healthy, adult, efavirenz, fenofibric acid, blood levels
Brief summary
Efavirenz is predominantly metabolized by cytochrome P450 (CYP) 2B6. Fenofibric Acid is an inhibitor of CYP 2B6. This study will evaluate the effect of multiple doses of fenofibric acid at steady-state on the pharmacokinetics of single-dose efavirenz in healthy adult subjects.
Detailed description
Efavirenz is predominantly metabolized by cytochrome P450 (CYP) 2B6. Fenofibric Acid is an inhibitor of CYP 2B6. This study will evaluate the effect of multiple doses of fenofibric acid at steady-state on the pharmacokinetics of single-dose efavirenz in healthy adult subjects. On study Day 1 after a fast of at least 10 hours, thirty healthy, non-smoking, non-obese, non-pregnant adult volunteers between the ages of 18 and 45 will be given one oral dose of efavirenz (1 x 600 mg tablet). Fasting will continue for 4 hours after the dose. Blood samples will be drawn from all participants before dosing and for 120 hours post-dose at times sufficient to adequately define the pharmacokinetics of efavirenz. A 21 day washout period will be completed after the first dose of efavirenz on Day 1. On Days 22 through 30, all subjects will receive a single oral dose of fenofibric acid (1 x 105 mg tablet) in the morning without regard to meals. On the morning of Day 31 after a fast of at least 10 hours, all study participants will receive co-administered single oral doses of efavirenz (1 x 600 mg tablet) and fenofibric acid (1 x 105 mg tablet). Fasting will continue for 4 hours after the dose. Blood samples will be drawn from all participants before dosing and for 120 hours post-dose at times sufficient to adequately determine the pharmacokinetics of efavirenz. A further goal of this study is to evaluate the safety and tolerability of this regimen in healthy volunteers. Subjects will be monitored throughout participation in the study for adverse reactions to the study drug and/or procedures. Vital signs (seated blood pressure and pulse) will be measured prior to dosing and at approximately 1, 2, 3 and 5 hours post-dose on Days 1 and 31 and prior to dosing and at approximately 1, 2 and 4 hours post-dose on Day 22 to coincide with peak plasma concentrations of both efavirenz and fenofibric acid. All adverse events whether elicited by query, spontaneously reported, or observed by clinic staff will be evaluated by the Investigator and reported in the subject's case report form.
Interventions
DRUGEfavirenz 600 mg
Efavirenz 600 mg administered as a single oral dose on the morning of Day 1.
DRUGFenofibric Acid
Co-administered single oral doses of Efavirenz 600 mg and Fenofibric Acid 105 mg on Day 31.
Sponsors
Mutual Pharmaceutical Company, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy adults 18-45 years of age * Non-smoking * Non-pregnant (post-menopausal, surgically sterile or using effective contraceptive measures) * Body mass index (BMI) less than 30 * Medically healthy on the basis of medical history and physical examination * Hemoglobin \> or = to 12g/dL * Completion of the screening process within 28 days prior to dosing * Provision of voluntary written informed consent
Exclusion criteria
* Recent participation (within 28 days) in other research studies * Recent significant blood donation or plasma donation * Pregnant or lactating * Test positive at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HbsAg), or hepatitis C virus (HCV) * Recent (2-year) history or evidence of alcoholism or drug abuse * History or presence of significant cardiovascular, pulmonary, hepatic, gallbladder or biliary tract, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or psychiatric disease * Subjects who have used any drugs or substances known to inhibit or induce cytochrome (CYP) P450 enzymes and/or P-glycoprotein (P-gp) within 28 days prior to the first dose and throughout the study * Drug allergies to fenofibric acid or efavirenz
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of Efavirenz | serial pharmacokinetic blood samples drawn prior to dosing on Days 1 and 31 and then 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96 and 120 hours after dose administration. | The maximum or peak concentration that efavirenz reaches in the plasma. |
| Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | serial pharmacokinetic blood samples drawn prior to dosing on Days 1 and 31 and then 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96 and 120 hours after dose administration | The area under the plasma concentration versus time curve from time 0 to the time of the last measurable concentration (t), as calculated by the linear trapezoidal rule for efavirenz. |
| Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | serial pharmacokinetic blood samples drawn immediately prior to dosing on Days 1 and 31 and then 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96 and 120 hours after dose administration | The area under the plasma concentration versus time curve from time 0 to infinity. \[AUC(0-∞)\] was calculated as the sum of AUC(0-t) plus the ratio of the last measurable plasma concentration to the elimination rate constant for efavirenz. |
Participant flow
Recruitment details
Thirty (30) healthy, non-smoking adult male and female volunteers from the community at-large were enrolled.
Pre-assignment details
Forty-nine (49) subjects were screened. Nineteen (19) were screen failures.
Participants by arm
| Arm | Count |
|---|---|
| Efavirenz Alone,Fenofibric Acid (FFA) Alone, Efavirenz and FFA On the morning of Day 1, subjects received a single dose of efavirenz 600 mg after an overnight fast of at least 10 hours, followed by a 21 day washout period. On the mornings of Days 22-30, subjects received a dose of fenofibric acid 105 mg without regard to meals. On the morning of Day 31, subjects received a co-administered single oral dose of efavirenz 600 mg and fenofibric acid 105 mg following an overnight fast of at least 10 hours. | 30 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| 1 Day Period Between Dosing | Adverse Event | 2 |
| 1 Day Period Between Dosing | Withdrawal by Subject | 1 |
| 21 Day Washout Period | Adverse Event | 1 |
| 21 Day Washout Period | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Efavirenz Alone,Fenofibric Acid (FFA) Alone, Efavirenz and FFA |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 30 Participants |
| Age Continuous | 26.8 years STANDARD_DEVIATION 6.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 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 | 27 Participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 12 / — | 7 / — | 8 / — |
| serious Total, serious adverse events | 0 / 30 | 0 / 28 | 0 / 25 |
Outcome results
Primary
Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)]
The area under the plasma concentration versus time curve from time 0 to infinity. \[AUC(0-∞)\] was calculated as the sum of AUC(0-t) plus the ratio of the last measurable plasma concentration to the elimination rate constant for efavirenz.
Time frame: serial pharmacokinetic blood samples drawn immediately prior to dosing on Days 1 and 31 and then 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96 and 120 hours after dose administration
Population: 30 subjects were exposed to study drugs. A total of 6 subjects withdrew. One of those 6 subjects completed all dosing of study medications but withdrew consent prior to the 8 hour post-dose activities on Day 31.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Efavirenz Alone | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 106,689.60 ng-hr/mL |
| Efavirenz With Fenofibric Acid | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 96,382.08 ng-hr/mL |
Primary
Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)]
The area under the plasma concentration versus time curve from time 0 to the time of the last measurable concentration (t), as calculated by the linear trapezoidal rule for efavirenz.
Time frame: serial pharmacokinetic blood samples drawn prior to dosing on Days 1 and 31 and then 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96 and 120 hours after dose administration
Population: 30 subjects were exposed to study drugs. A total of 6 subjects withdrew. One of those 6 subjects completed all dosing of study medications but withdrew consent prior to the 8 hour post-dose activities on Day 31.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Efavirenz Alone | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 70,144.35 ng-hr/mL |
| Efavirenz With Fenofibric Acid | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 63,313.23 ng-hr/mL |
Primary
Maximum Plasma Concentration (Cmax) of Efavirenz
The maximum or peak concentration that efavirenz reaches in the plasma.
Time frame: serial pharmacokinetic blood samples drawn prior to dosing on Days 1 and 31 and then 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96 and 120 hours after dose administration.
Population: 30 subjects were enrolled in this study. A total of 6 subjects withdrew. One of those 6 subjects completed all dosing of study interventions but withdrew consent prior to the 8 hour post-dose activities on Day 31.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Efavirenz Alone | Maximum Plasma Concentration (Cmax) of Efavirenz | 2,461.58 ng/mL | Standard Deviation 655.13 |
| Efavirenz With Fenofibric Acid | Maximum Plasma Concentration (Cmax) of Efavirenz | 2,384.79 ng/mL | Standard Deviation 573.73 |