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

This study has been completed.
Sponsor:
Information provided by:
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00017758
First received: June 11, 2001
Last updated: March 13, 2006
Last verified: February 2004
  Purpose

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.


Condition Intervention Phase
HIV Infections
HIV Seronegativity
Lipodystrophy
Drug: Pravastatin sodium
Drug: Simvastatin
Drug: Atorvastatin calcium
Drug: Nelfinavir mesylate
Drug: Efavirenz
Phase 1

Study Type: Interventional
Study Design: Primary Purpose: Treatment
Official Title: The Effect of Efavirenz and Nelfinavir on the Pharmacokinetics of Hydroxymethylglutaryl Coenzyme A Reductase Inhibitors

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Estimated Enrollment: 56
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.

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00017758

Locations
United States, California
Stanford Univ Med Ctr
Stanford, California, United States, 943055107
United States, Colorado
Univ of Colorado Health Sciences Ctr
Denver, Colorado, United States, 80262
United States, Maryland
Johns Hopkins Hosp
Baltimore, Maryland, United States, 21287
United States, Minnesota
Univ of Minnesota
Minneapolis, Minnesota, United States, 55455
United States, Missouri
Washington Univ / St Louis Connect Care
Saint Louis, Missouri, United States, 63108
Washington Univ School of Medicine
St Louis, Missouri, United States, 63108
United States, New York
Univ of Rochester Medical Center
Rochester, New York, United States, 14642
United States, Ohio
Univ of Cincinnati
Cincinnati, Ohio, United States, 452670405
United States, Pennsylvania
Univ of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15213
United States, Washington
Univ of Washington
Seattle, Washington, United States, 98104
Sponsors and Collaborators
Investigators
Study Chair: John Gerber
Study Chair: Judith Aberg
  More Information

Additional Information:
Publications:
ClinicalTrials.gov Identifier: NCT00017758     History of Changes
Other Study ID Numbers: ACTG A5108, AACTG A5108
Study First Received: June 11, 2001
Last Updated: March 13, 2006
Health Authority: United States: Federal Government

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Drug Interactions
Nelfinavir
Reverse Transcriptase Inhibitors
Anti-HIV Agents
Pharmacokinetics
Pravastatin
efavirenz
Simvastatin
atorvastatin
Hydroxymethylglutaryl-CoA Reductase Inhibitors

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Lipodystrophy
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Skin Diseases, Metabolic
Skin Diseases
Lipid Metabolism Disorders
Metabolic Diseases
Hypolipidemic Agents
Simvastatin
Atorvastatin
Pravastatin
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Nelfinavir
Efavirenz
Reverse Transcriptase Inhibitors
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Lipid Regulating Agents
Therapeutic Uses
Anticholesteremic Agents

ClinicalTrials.gov processed this record on April 14, 2014