Healthy
Conditions
Brief summary
Efavirenz is predominantly metabolized by cytochrome P450 (CYP) 2B6. Fenofibric Acid is an inhibitor of CYP2B6. 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 CYP2B6. 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. This study will not evaluate the the effects of efavirenz on fenofibric acid pharmacokinetics. 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 24 hours post-dose on a confined basis at times sufficient to adequately define the pharmacokinetics of efavirenz. Blood sampling will then continue on a non-confined basis at 48, 72, 96 and 120 hours post-dose. 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 24 hours post-dose on a confined basis at times sufficient to adequately determine the pharmacokinetics of efavirenz. Blood sampling will then continue on a non-confined basis at 48, 72, 96 and 120 hours post-dose. 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, 22 and 31 to coincide with peak plasma concentrations of both efavirenz and fenofibric acid. Blood pressure and pulse will also be obtained at 24 hours post-dose on Days 2 and 32 prior to discharge from the clinical study unit. 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
DRUGfenofibric acid 105 mg
fenofibric acid 105 mg
Sponsors
Mutual Pharmaceutical Company, Inc.
Study design
Allocation
NON_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 and non-pregnant (post-menopausal, surgically sterile or using effective contraceptive measures), with a body mass index (BMI) greater or equal to 18 and less than or equal to 32kg/m2, hemoglobin \>12 g/dL.
Exclusion criteria
* recent participation (within past month) 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, psychiatric disease or active sexually transmitted 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 or sensitivities to efavirenz, fenofibrate, fenofibric acid or any component of the two formulations * Subjects who have had a tattoo or body piercing within 30 days prior to administration of study medication
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics: Maximum Plasma Concentration (Cmax) | serial pharmacokinetic blood samples drawn immediately prior to dosing on Days 1 and 31 and then 0.5, 1, 1.5, 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 the drug reaches in the plasma for efavirenz |
| Pharmacokinetics: Area Under the Concentration Versus Time Curve From Time 0 to Time t[AUC(0-t)] | serial pharmacokinetic blood samples drawn immediately prior to dosing on Days 1 and 31 and then 0.5, 1, 1.5, 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 |
| Pharmacokinetics: Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-infinity] | 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. \[AUC(0 to infinity)\] 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. |
Countries
United States
Participant flow
Recruitment details
Thirty (30) healthy, non-smoking adult male and female volunteers from the community at-large were enrolled
Participants by arm
| Arm | Count |
|---|---|
| Efavirenz Alone, FFA Alone, Enfavirenz and FFA Together 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 | Protocol Violation | 1 |
| Efavirenz Alone | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Efavirenz Alone, FFA Alone, Enfavirenz and FFA Together |
|---|---|
| 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 7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 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 | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 24 Participants |
| Region of Enrollment United States | 30 participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 14 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 | 19 / 30 | 2 / 29 | 15 / 28 |
| serious Total, serious adverse events | 0 / 30 | 0 / 29 | 0 / 28 |
Outcome results
Primary
Pharmacokinetics: Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-infinity]
The area under the plasma concentration versus time curve from time 0 to infinity. \[AUC(0 to infinity)\] 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: 28 of 30 subjects completed the entire study and had sufficient data to calculate at minimum the area under the plasma concentration versus time curve from time 0 to infinity for efavirenz.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Efavirenz Alone | Pharmacokinetics: Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-infinity] | 121 h*ug/mL | Standard Deviation 33.6 |
| Efavirenz With Fenofibric Acid | Pharmacokinetics: Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-infinity] | 112 h*ug/mL | Standard Deviation 30.3 |
Primary
Pharmacokinetics: 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 immediately prior to dosing on Days 1 and 31 and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96, and 120 hours after dose administration
Population: 28 of 30 subjects completed the entire study and had sufficient data to calculate at minimum the area under the plasma concentration versus time curve from time 0 to the time t of the last quantifiable concentration (AUC0-t) for efavirenz.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Efavirenz Alone | Pharmacokinetics: Area Under the Concentration Versus Time Curve From Time 0 to Time t[AUC(0-t)] | 70.58 h*ug/mL | Standard Deviation 17.28 |
| Efavirenz With Fenofibric Acid | Pharmacokinetics: Area Under the Concentration Versus Time Curve From Time 0 to Time t[AUC(0-t)] | 64.62 h*ug/mL | Standard Deviation 15.22 |
Primary
Pharmacokinetics: Maximum Plasma Concentration (Cmax)
The maximum or peak concentration that the drug reaches in the plasma for efavirenz
Time frame: serial pharmacokinetic blood samples drawn immediately prior to dosing on Days 1 and 31 and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96, and 120 hours after dose administration
Population: 28 of 30 subjects completed the entire study and had sufficient data to calculate at minimum the maximum concentration (Cmax)for efavirenz.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Efavirenz Alone | Pharmacokinetics: Maximum Plasma Concentration (Cmax) | 2.62 ug/mL | Standard Deviation 0.57 |
| Efavirenz With Fenofibric Acid | Pharmacokinetics: Maximum Plasma Concentration (Cmax) | 2.63 ug/mL | Standard Deviation 0.55 |