The Effect of Efavirenz and Nelfinavir on the Blood Levels of Certain Lipid-Lowering Drugs
Condition: HIV Infections; HIV Seronegativity; Lipodystrophy
MeSH terms: Lipodystrophy
Study type: Interventional
Phase: Phase 1

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.
    

Intervention name(s): Pravastatin sodium; Simvastatin; Atorvastatin calcium; Nelfinavir mesylate; Efavirenz
Intervention type(s): Drug; Drug; Drug; Drug; Drug
Intervention MeSH terms: Efavirenz; Nelfinavir; Atorvastatin; Simvastatin; Pravastatin; Calcium
Primary purpose: Treatment
Keywords: Drug Interactions; Nelfinavir; Reverse Transcriptase Inhibitors; Anti-HIV Agents; Pharmacokinetics; Pravastatin; efavirenz; Simvastatin; atorvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors