The Effect of Efavirenz and Nelfinavir on the Blood Levels of Certain Lipid-Lowering Drugs
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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 |
| Estimated Enrollment: | 56 |
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 |
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| 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 | |
| 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 March 07, 2013
