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The Effect of Efavirenz and Nelfinavir on the Blood Levels of Certain Lipid-Lowering Drugs

Primary Purpose

HIV Infections, HIV Seronegativity, Lipodystrophy

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Pravastatin sodium
Simvastatin
Atorvastatin calcium
Nelfinavir mesylate
Efavirenz
Sponsored by
National Institute of Allergy and Infectious Diseases (NIAID)
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional treatment trial for HIV Infections focused on measuring Drug Interactions, Nelfinavir, Reverse Transcriptase Inhibitors, Anti-HIV Agents, Pharmacokinetics, Pravastatin, efavirenz, Simvastatin, atorvastatin, Hydroxymethylglutaryl-CoA Reductase Inhibitors

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria Volunteers may be eligible for this study if they: Are HIV-negative. Are 18 to 60 years old. Weigh at least 50 kg (110 lbs) and are within 30 percent of their ideal body weight. Cannot have children (have reached menopause [change of life] for at least 24 straight months or have had a hysterectomy), if female and enrolling to Group A, B, or C. Have a negative pregnancy test within 14 days before study entry and within 24 hours before starting the study drugs, if female, able to have children, and enrolling to Group D. Agree to avoid trying to become pregnant or causing someone to become pregnant. Agree not to donate sperm or participate in other fertilization procedures. If participating in sexual activity that could lead to pregnancy, the study volunteer and/or partner must use 2 reliable methods of birth control at the same time, while taking study drugs, and for 6 weeks after stopping the drugs. Male volunteers are allowed to be sexually active without the use of birth control if they have had a successful vasectomy or are sterile. Exclusion Criteria Volunteers will not be eligible for this study if they: Have or have had heart, kidney, blood, nerve, digestive, mental, hormonal, or immune system diseases. These include high blood pressure, blocked arteries, arthritis, diabetes, stomach or intestinal problems, depression, and past use of antidepressant drugs. Are pregnant or breast-feeding. Have used experimental, prescription, or over-the-counter drugs within 14 days before study entry, except for aspirin (ASA), acetaminophen (Tylenol), diphenhydramine (Benadryl), daily multivitamins, mineral supplements, birth control pills or implants, and hormone replacement therapy for women who have reached menopause. Are allergic to study drugs or their ingredients. Abuse drugs or alcohol. Have a medical condition that, in the opinion of the investigator, would interfere with their participation in the study. Have participated in any experimental drug study within 30 days before study entry. Are not able to keep their usual diet during the study or are unable to write down their food intake before the study visits. Have an abnormal urine test result, e.g., urinary tract infection, kidney disease, or kidney stones.

Sites / Locations

  • Stanford Univ Med Ctr
  • Univ of Colorado Health Sciences Ctr
  • Johns Hopkins Hosp
  • Univ of Minnesota
  • Washington Univ / St Louis Connect Care
  • Washington Univ School of Medicine
  • Univ of Rochester Medical Center
  • Univ of Cincinnati
  • Univ of Pittsburgh
  • Univ of Washington

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

First Posted
June 11, 2001
Last Updated
March 13, 2006
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT00017758
Brief Title
The Effect of Efavirenz and Nelfinavir on the Blood Levels of Certain Lipid-Lowering Drugs
Official Title
The Effect of Efavirenz and Nelfinavir on the Pharmacokinetics of Hydroxymethylglutaryl Coenzyme A Reductase Inhibitors
Study Type
Interventional

2. Study Status

Record Verification Date
February 2004
Overall Recruitment Status
Completed
Study Start Date
undefined (undefined)
Primary Completion Date
undefined (undefined)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

5. Study Description

Brief Summary
The purpose of this study is to find out whether certain anti-HIV drugs (efavirenz [EFV] and nelfinavir [NFV]) affect the amount of certain fat-lowering drugs (atorvastatin, pravastatin, and simvastatin) in the blood. Protease inhibitors (PIs), a type of anti-HIV drug, are known to cause increased lipids (fats) in the blood of HIV-infected patients. EFV also is known to increase blood fats. HIV-infected patients who take PIs and/or EFV may need to take fat-lowering drugs to correct this problem. So it is important to look at possible drug interactions when these drugs are taken together. This study will see if taking EFV or NFV, a protease inhibitor, affects the blood level of simvastatin, atorvastatin, or pravastatin (all fat-lowering drugs). To obtain results more quickly, the study population will be healthy HIV-negative volunteers.
Detailed Description
Abnormalities in lipid metabolism are a recognized side effect of protease inhibitor (PI) therapy in HIV-infected patients. EFV also is known to increase plasma cholesterol. In an attempt to normalize serum lipids in HIV-infected patients on PIs and/or EFV, Hydroxymethylglutaryl Coenzyme A (HMG-CoA) reductase inhibitors (also known as statins) may be prescribed. Therefore, it is important to study how PIs and EFV affect the PK of concurrently-administered statins. Many of the statins utilize the cytochrome P450 (CYP) 3A4 enzyme for metabolism. In addition, atorvastatin and simvastatin have active metabolites, generated via CYP3A4, that contribute to the drugs' lipid-lowering activity and probably to their toxicity. Pravastatin is not metabolized by CYP3A4 but is inactivated by conjugation, non-CYP3A4-induced hydroxylation, and renal excretion. NFV, the most commonly used PI, is an inhibitor of CYP3A4 and an inducer of other CYPs and conjugative pathways. EFV is a mixed CYP3A4 inhibitor and inducer. This study examines the effect of NFV on the PK of pravastatin and the effect of EFV on the PK of simvastatin, atorvastatin, and pravastatin. As EFV with pravastatin is expected to be a common drug combination during the treatment of HIV infection, it should be explored further, even though drug interactions are not expected. To expedite this study, the study population is comprised of healthy control volunteers. Volunteers are assigned to 1 of 4 groups. Volunteers in Groups A, B, and C take a statin (simvastatin, atorvastatin, or pravastatin, respectively) on Days 0 to 3. After Day 3, the statin is stopped and EFV is begun. Volunteers take EFV until Day 14 and the statin and EFV together from Days 15 to 18. Volunteers in Group D take pravastatin on Days 0 to 3, NFV on Days 4 to 12, and pravastatin and NFV together on Days 13 to 16. Fasting lipid profiles are performed on Days 0, 4, 15, and 19 for Groups A, B, and C, and on Days 0, 3, 13, and 16 for Group D. PK sampling is performed on Days 3, 14, and 18 for Groups A, B, and C (requiring an overnight stay), and on Days 3 and 16 for Group D. Volunteers receive monetary compensation for participation in this study.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV Infections, HIV Seronegativity, Lipodystrophy
Keywords
Drug Interactions, Nelfinavir, Reverse Transcriptase Inhibitors, Anti-HIV Agents, Pharmacokinetics, Pravastatin, efavirenz, Simvastatin, atorvastatin, Hydroxymethylglutaryl-CoA Reductase Inhibitors

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Enrollment
56 (false)

8. Arms, Groups, and Interventions

Intervention Type
Drug
Intervention Name(s)
Pravastatin sodium
Intervention Type
Drug
Intervention Name(s)
Simvastatin
Intervention Type
Drug
Intervention Name(s)
Atorvastatin calcium
Intervention Type
Drug
Intervention Name(s)
Nelfinavir mesylate
Intervention Type
Drug
Intervention Name(s)
Efavirenz

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria Volunteers may be eligible for this study if they: Are HIV-negative. Are 18 to 60 years old. Weigh at least 50 kg (110 lbs) and are within 30 percent of their ideal body weight. Cannot have children (have reached menopause [change of life] for at least 24 straight months or have had a hysterectomy), if female and enrolling to Group A, B, or C. Have a negative pregnancy test within 14 days before study entry and within 24 hours before starting the study drugs, if female, able to have children, and enrolling to Group D. Agree to avoid trying to become pregnant or causing someone to become pregnant. Agree not to donate sperm or participate in other fertilization procedures. If participating in sexual activity that could lead to pregnancy, the study volunteer and/or partner must use 2 reliable methods of birth control at the same time, while taking study drugs, and for 6 weeks after stopping the drugs. Male volunteers are allowed to be sexually active without the use of birth control if they have had a successful vasectomy or are sterile. Exclusion Criteria Volunteers will not be eligible for this study if they: Have or have had heart, kidney, blood, nerve, digestive, mental, hormonal, or immune system diseases. These include high blood pressure, blocked arteries, arthritis, diabetes, stomach or intestinal problems, depression, and past use of antidepressant drugs. Are pregnant or breast-feeding. Have used experimental, prescription, or over-the-counter drugs within 14 days before study entry, except for aspirin (ASA), acetaminophen (Tylenol), diphenhydramine (Benadryl), daily multivitamins, mineral supplements, birth control pills or implants, and hormone replacement therapy for women who have reached menopause. Are allergic to study drugs or their ingredients. Abuse drugs or alcohol. Have a medical condition that, in the opinion of the investigator, would interfere with their participation in the study. Have participated in any experimental drug study within 30 days before study entry. Are not able to keep their usual diet during the study or are unable to write down their food intake before the study visits. Have an abnormal urine test result, e.g., urinary tract infection, kidney disease, or kidney stones.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John Gerber
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Judith Aberg
Official's Role
Study Chair
Facility Information:
Facility Name
Stanford Univ Med Ctr
City
Stanford
State/Province
California
ZIP/Postal Code
943055107
Country
United States
Facility Name
Univ of Colorado Health Sciences Ctr
City
Denver
State/Province
Colorado
ZIP/Postal Code
80262
Country
United States
Facility Name
Johns Hopkins Hosp
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Univ of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Washington Univ / St Louis Connect Care
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63108
Country
United States
Facility Name
Washington Univ School of Medicine
City
St Louis
State/Province
Missouri
ZIP/Postal Code
63108
Country
United States
Facility Name
Univ of Rochester Medical Center
City
Rochester
State/Province
New York
ZIP/Postal Code
14642
Country
United States
Facility Name
Univ of Cincinnati
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
452670405
Country
United States
Facility Name
Univ of Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States
Facility Name
Univ of Washington
City
Seattle
State/Province
Washington
ZIP/Postal Code
98104
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
16514303
Citation
Aberg JA, Rosenkranz SL, Fichtenbaum CJ, Alston BL, Brobst SW, Segal Y, Gerber JG; ACTG A5108 team. Pharmacokinetic interaction between nelfinavir and pravastatin in HIV-seronegative volunteers: ACTG Study A5108. AIDS. 2006 Mar 21;20(5):725-9. doi: 10.1097/01.aids.0000216373.53819.92.
Results Reference
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The Effect of Efavirenz and Nelfinavir on the Blood Levels of Certain Lipid-Lowering Drugs

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