A Drug-Drug Interaction Study Between Fenofibric Acid and Efavirenz

• Sponsor: Mutual Pharmaceutical Company, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01472380
• Collaborator: (none)
• Enrollment: 30
• Location: 1
• Arms: 2
• Duration (Months): 2
• Patients Per Site Per Month: 15

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: efavirenz; Drug: fenofibric acid 105 mg	Phase 1

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: An Open-label, Drug Interaction Study to Investigate the Effects of Steady-State Fenofibric Acid on the Single-Dose Pharmacokinetics of Efavirenz in Healthy Subjects
• Study Start Date: Nov 1, 2011
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: Jan 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Efavirenz 600mg alone efavirenz 600mg by mouth taken on Day 1	Drug: efavirenz; 600 mg; Other Names: SUSTIVA
Active Comparator: Efavirenz co-administered with fenofibric acid co-administered oral doses of efavirenz 600 mg and fenofibric acid 105 mg taken on Day 31	Drug: efavirenz; 600 mg; Other Names: SUSTIVA ; Drug: fenofibric acid 105 mg; fenofibric acid 105 mg; Other Names: FIBRICOR

Outcome Measures

Primary Outcome Measures

1. 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

2. 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

3. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	INC Research	Morgantown	West Virginia	United States	26505

Sponsors and Collaborators

• Mutual Pharmaceutical Company, Inc.

Investigators

• Study Chair: Matthew Davis, MD, Mutual Pharmaceutical Company, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mutual Pharmaceutical Company, Inc.
• ClinicalTrials.gov Identifier: NCT01472380
• Other Study ID Numbers: MPC-028-11-1001
• First Posted: Nov 16, 2011
• Last Update Posted: Aug 1, 2012
• Last Verified: Jul 1, 2012

• Additional relevant MeSH terms: Efavirenz; Fenofibric acid

Study Results

Participant Flow

Recruitment Details	Thirty (30) healthy, non-smoking adult male and female volunteers from the community at-large were enrolled

Arm/Group Title	Efavirenz Alone, FFA Alone, Enfavirenz and FFA Together
Arm/Group Description	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
Period Title: Efavirenz Alone
STARTED	30
COMPLETED	29
NOT COMPLETED	1
Period Title: Efavirenz Alone
STARTED	29
COMPLETED	29
NOT COMPLETED	0
Period Title: Efavirenz Alone
STARTED	29
COMPLETED	28
NOT COMPLETED	1
Period Title: Efavirenz Alone
STARTED	28
COMPLETED	28
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Efavirenz Alone, FFA Alone, Enfavirenz and FFA Together
Arm/Group Description	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
Overall Participants	30
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	30 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	26.8 (7.0)
Sex: Female, Male (Count of Participants)
Female	16 53.3%
Male	14 46.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 3.3%
Not Hispanic or Latino	29 96.7%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 3.3%
Native Hawaiian or Other Pacific Islander	1 3.3%
Black or African American	3 10%
White	24 80%
More than one race	0 0%
Unknown or Not Reported	1 3.3%
Region of Enrollment (participants) [Number]
United States	30 100%

Outcome Measures

1. Primary Outcome

Title	Pharmacokinetics: Maximum Plasma Concentration (Cmax)
Description	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

Outcome Measure Data

Analysis Population Description

28 of 30 subjects completed the entire study and had sufficient data to calculate at minimum the maximum concentration (Cmax)for efavirenz.

Arm/Group Title	Efavirenz Alone	Efavirenz With Fenofibric Acid
Arm/Group Description	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 morning of Day 31, subjects received a co-administered single oral dose of efavirenz 600 mg and fenofibric acid 105 mg after an overnight fast.
Measure Participants	28	28
Mean (Standard Deviation) [ug/mL]	2.62 (0.57)	2.63 (0.55)

2. Primary Outcome

Title	Pharmacokinetics: Area Under the Concentration Versus Time Curve From Time 0 to Time t[AUC(0-t)]
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Efavirenz Alone	Efavirenz With Fenofibric Acid
Arm/Group Description	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 morning of Day 31, subjects received a co-administered single oral dose of efavirenz 600 mg and fenofibric acid 105 mg after an overnight fast.
Measure Participants	28	28
Mean (Standard Deviation) [h*ug/mL]	70.58 (17.28)	64.62 (15.22)

3. Primary Outcome

Title	Pharmacokinetics: Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-infinity]
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Efavirenz Alone	Efavirenz With Fenofibric Acid
Arm/Group Description	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 morning of Day 31, subjects received a co-administered single oral dose of efavirenz 600 mg and fenofibric acid 105 mg after an overnight fast.
Measure Participants	28	28
Mean (Standard Deviation) [h*ug/mL]	121 (33.6)	112 (30.3)

Adverse Events

Arm/Group Title	Efavirenz Alone		Fenofibric Acid Alone		Efavirenz With Fenofibric Acid
Arm/Group Description	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 after an overnight fast.
All Cause Mortality
	Efavirenz Alone		Fenofibric Acid Alone		Efavirenz With Fenofibric Acid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Efavirenz Alone		Fenofibric Acid Alone		Efavirenz With Fenofibric Acid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		0/29 (0%)		0/28 (0%)
Other (Not Including Serious) Adverse Events
	Efavirenz Alone		Fenofibric Acid Alone		Efavirenz With Fenofibric Acid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/30 (63.3%)		2/29 (6.9%)		15/28 (53.6%)
Eye disorders
Vision blurred	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Gastrointestinal disorders
Abdominal pain upper	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Nausea	2/30 (6.7%)	2	0/29 (0%)	0	0/28 (0%)	0
Vomiting	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Investigations
Alanine aminotransferase increased	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Aspartate aminotransferase	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Blood pressure increased	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Nervous system disorders
Dizziness	15/30 (50%)	17	0/29 (0%)	0	8/28 (28.6%)	8
Headache	6/30 (20%)	6	2/29 (6.9%)	2	6/28 (21.4%)	6
Somnolence	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Psychiatric disorders
Euphoric Mood	0/30 (0%)	0	0/29 (0%)	0	5/28 (17.9%)	5
Reproductive system and breast disorders
Dysmenorrhea	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Skin and subcutaneous tissue disorders
Hyperhidrosis	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Vascular disorders
Hot flush	0/30 (0%)	0	0/29 (0%)	0	4/28 (14.3%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.