Effect of Genetics on Metabolism of Efavirenz

NCT00245986 | Completed Phase 4

• 2 other identifiers: 06000606-CC-0006
• Study Type: interventional
• Target: 350
• Locations: 1 country
• Sites: 1

Brief Summary

This study will evaluate the effects of genetics on metabolism of the anti-HIV medicine efavirenz (Sustiva) and will see if Efavirenz interacts with bupropion (Zyban or Wellbutrin), a drug commonly used to treat depression and to help people quit smoking. Efavirenz is metabolized by an enzyme called CYP2B6, which is thought to be more active in some people than in others, depending on their genetic makeup. The rate of metabolism of the drug can affect how the body responds it and perhaps the ability of the HIV virus to develop resistance to it. Healthy volunteers between 18 and 55 years of age who are non-smokers and HIV-infected men and women 18 years of age and older who are taking efavirenz along with two or three nucleoside reverse transcriptase inhibitors may be eligible for this study. Candidates are screened with a medical history and physical examination and blood tests, including tests to determine which genes they have for four different proteins or enzymes (CYP2B6, CYP3A4, CYP3A5, and MDR1) that metabolize drugs. Participants are assigned to one of three groups for the following procedures:

• HIV-infected individuals: Blood samples are drawn to measure efavirenz levels, as follows: On the last day of taking efavirenz, the subject skips his or her usual evening efavirenz dose the night before sampling. The next morning at clinic, a catheter (flexible plastic tube) is inserted into a vein in the subject's arm for collecting blood samples. After the first sample is drawn, the subject takes a dose of efavirenz. Eight more blood samples are collected at 1, 2, 4, 6, 8, 12, 24 and 48 hours after taking the efavirenz tablet. (The catheter is removed after the 12-hour sample and the subject is discharged home, and then returns to the clinic for the 24- and 48-hour samples, which are collected through a needle inserted into an arm vein.) The subject returns to the clinic four more times for a single blood draw at 7, 14, 21 and 28 days after stopping efavirenz. HIV-infected patients whose HIV viral load reaches 1,000 copies/L or more within 12 months after completing the study are asked to return to the clinic for a blood draw to check the genotype of the virus for drug resistance.
• Healthy Volunteers - Group 1: Blood samples are drawn to measure efavirenz levels, as follows: Participants take one efavirenz tablet once a day for 13 to 15 days. On the last day of taking efavirenz, the subject takes his/her last dose of efavirenz in clinic, where blood is then collected as described above for HIV-infected individuals.
• Healthy Volunteers - Group 2: A catheter is inserted into a vein in the subject's arm and a blood sample is drawn through the catheter. The subject then takes a single bupropion tablet and additional blood samples are drawn at 1,2, 2.5, 3, 3.5, 4, 6, 8, 12, 24 and 48 hours after the dose to measure the amount of drug in the blood. Subjects begin taking efavirenz 0 to 6 days after the last bupropion blood level is measured. As above, subjects will take one efavirenz tablet once a day for 13 to 15 days. On the last day of taking efavirenz, a catheter is inserted into the subject's arm. Two blood samples are drawn through the catheter, the subject takes the daily dose of efavirenz along with a bupropion tablet. Eleven additional blood samples are drawn at 1, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, and 48 hours after taking the pills to measure blood levels of bupropion. Eight additional samples are collected at 1, 2, 4, 6, 8, 12, 24, and 48 hours to measure efavirenz blood levels. (The catheter is removed after the 12-hour sample and the subject is discharged home; the 24- and 48-hour samples are collected through a needle inserted into an arm vein.)

Conditions

Metabolism

Keywords

Pharmacokinetics; Cytochrome P450; HIV Resistance; Drug Interaction; Non-Nucleoside Reverse Transcriptase Inhibitors; HIV Positive; Healthy Volunteer; HV

Interventions

Blood draw PROCEDURE

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Males and females between the ages of 18 and 55 years.
• Healthy by medical history and physical exam
• Laboratory values within established guidelines for participation in clinical studies: AST less than 1.25 x ULN; SCr less than or equal to ULN; hemoglobin equal to or greater than 11 g/dL (for males and females).
• ) Ability to abstain from eating grapefruit or drinking grapefruit juice during EFV administration and EFV PK sampling periods.
• ) Negative serum pregnancy test for females of child-bearing potential (within 1 day before starting EFV).
• ) Females of child-bearing potential who are able and willing to either practice abstinence or use two non-hormonal forms of birth control (such as condoms, diaphragms, IUDs, etc.) while taking EFV and up to the 28th day after their last EFV dose.
• ) Non-smokers for at least 1 month prior to study participation.

You may not qualify if:

• Concomitant routine therapy with any prescription, over-the-counter, herbal, or holistic medications, including oral contraceptives and hormonal IUDs, for 14 days prior to study participation.
• Intermittent use of acetaminophen and non-steroidal anti-inflammatory medications (i.e. ibuprofen) will be allowed during the study, but should not be taken on the days of pharmacokinetic blood sampling. Intermittent use of the non-sedating antihistamines fexofenadine and cetirizine and topical hydrocortisone cream will be allowed during the study under the supervision of and with the approval of the study team; however, fexofenadine and cetirizine should not be taken on the days of pharmacokinetic blood sampling.
• A daily multivitamin with minerals will be allowed during the study.
• Inability to obtain venous access for blood sample collection.
• The presence or history of any of the following: HIV infection, active tuberculosis, renal disease (chronic or acute renal failure or insufficiency), diabetes, hepatitis B or C infection (as assessed by patient interview) or hepatic impairment, pancreatitis, peptic ulcer disease requiring maintenance pharmacologic therapy, injection drug use, epilepsy or seizure disorders, history of head trauma, any psychiatric illness or symptoms (including, but not limited to depression, bipolar disorder, a history of suicide attempts or suicidal ideation, psychosis, schizophrenia, and bulimia or anorexia nervosa) as assessed by patient interview and through clinician evaluation using the Beck Depression Index, or any other condition that may interfere with the interpretation of the study results or not be in the best interest of the subject in the opinion of the investigators.
• Positive pregnancy test or breastfeeding female.
• A previously documented history of persistent diarrhea or malabsorption that would interfere with the subject's ability to absorb drugs.
• Drug or alcohol abuse that may impair safety or adherence or interfere with the study results (more than 3 alcoholic drinks per day on a regular basis).
• History of intolerance or allergic reaction to efavirenz (Sustiva® (Registered Trademark)) or bupropion (Wellbutrin® (Registered Trademark)).
• HIV-infected volunteers:
• HIV-positive males and females at least 18 years old.
• On a standard EFV-containing regimen (EFV + 2 or 3 NRTIs) for at least 1 month prior to study participation.
• Laboratory values within established guidelines for participation in clinical studies53: AST less than or equal to 1.25 x ULN; SCr less than or equal to ULN; hemoglobin equal to or greater than 11 g/dL (for both males and females).
• Ability to abstain from eating grapefruit or drinking grapefruit juice during the EFV PK sampling period and for 3 days prior.
• A negative pregnancy test for women of child-bearing potential.

Sponsors & Collaborators

• National Institutes of Health Clinical Center (CC): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (1)

• Haas DW, Fessel WJ, Delapenha RA, Kessler H, Seekins D, Kaplan M, Ruiz NM, Ploughman LM, Labriola DF, Manion DJ. Therapy with efavirenz plus indinavir in patients with extensive prior nucleoside reverse-transcriptase inhibitor experience: a randomized, double-blind, placebo-controlled trial. J Infect Dis. 2001 Feb 1;183(3):392-400. doi: 10.1086/318083. Epub 2000 Dec 29.

  PMID: 11133370 BACKGROUND

MeSH Terms

Conditions

HIV Seropositivity

Interventions

Blood Specimen Collection

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Study Design

• Study Type: interventional
• Phase: phase 4
• Purpose: TREATMENT
• Sponsor Type: NIH

Study Record Dates

• First Submitted: October 27, 2005
• First Posted: October 28, 2005
• Study Start: October 18, 2005
• Study Completion: May 20, 2008
• Last Updated: July 2, 2017

Record last verified: 2008-05-20

Locations

US (1)