The Influence of Ritonavir, Alone and in Combination With Lopinavir, on Fenofibric Acid Pharmacokinetics in Healthy Volunteers
Condition: HIV; Fenofibrate; Protease Inhibitors; Hypertriglyceridemia; Glucuronosyltransferase
MeSH terms: Hypertriglyceridemia
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      - Patients infected with the human immunodeficiency virus (HIV) are often treated with
      protease inhibitors that help fight HIV infection. However, these medications often increase
      blood cholesterol levels, particularly triglycerides and low-density lipoproteins, and can
      lead to heart disease and other problems. Patients may take drugs known as fibrates (such as
      gemfibrozil (Lopid )) to lower triglyceride levels, but even with maximum approved doses
      patients often cannot reach goal triglyceride levels. Research suggests that fibrates and
      certain HIV medications, such as ritonavir and lopinavir/ritonavir, may interact and decrease
      the effectiveness of the fibrate treatment. More research is needed to determine the best
      drug to lower triglyceride levels in HIV patients who are receiving protease inhibitor
      therapy.

      Objectives:

      - To evaluate the drug-drug interaction between fenofibrate and protease inhibitors
      lopinavir/ritonavir and ritonavir.

      Eligibility:

      - Healthy individuals between 18 and 60 years of age.

      Design:

        -  This study will require a screening visit and 18 study visits. The screening visit will
           take 3 to 4 hours, and can occur 7 to 30 days before starting the study. The rest of the
           study, not including the screening visit, is 48 days. Three of the visits will take
           about 12 hours, and the remaining 15 visits will take about 1 hour.

        -  For study days 1 to 7, participants will take fenofibrate alone. Participants will keep
           a daily record of medication doses and any side effects.

        -  For study days 8 to 27, participants will take fenofibrate and ritonavir. Participants
           will keep a daily record of medication doses and any side effects.

        -  For study days 29 to 48, participants will take fenofibrate and lopinavir/ritonavir.
           Participants will keep a daily record of medication doses and any side effects.

        -  Participants will have regular study visits to provide blood samples for research and
           monitoring.
    

Detailed description: 
      Highly active antiretroviral therapy (HAART) has enhanced the life expectancy of human
      immunodeficiency virus (HIV) infected patients, making HIV a manageable chronic disease for
      many patients. Patients with HIV are prone to lipid abnormalities secondary to HIV infection
      and antiretroviral therapy, particularly HIV protease inhibitors (PI). PI containing regimens
      that contain boosting doses of ritonavir (RTV) (i.e., 100 200 mg once or twice daily) often
      cause significant increases in total cholesterol, low density lipoprotein cholesterol, and
      triglycerides. Therapy for isolated hypertriglyceridemia includes fibric acid derivatives,
      such as gemfibrozil (GFZ) or fenofibrate; however, despite treatment with these agents,
      triglyceride levels often remain elevated in HIV infected patients treated with HAART. Many
      factors likely contribute to the incomplete effectiveness of fibrates in these patients. One
      possible contributing factor may be a clinically significant interaction between HAART and
      fibrates. We recently reported a mean 41 percent decrease in GFZ area under the curve when
      administered with the PI combination lopinavir/ritonavir (LPV/r). To determine whether a
      similar interaction exists with fenofibrate, this study will characterize the impact of RTV
      and LPV/r on the pharmacokinetic (PK) profile of fenofibrate (Tricor formulation), after a
      single 145 mg oral dose, administered to healthy volunteers. In a single sequence study
      design, 13 subjects will receive a single 145 mg dose of fenofibrate on three occasions:
      before and after 14 days of RTV 100 mg twice daily, and after 14 days of LPV/r 400/100 mg
      twice daily. With the exclusion of the screening period, the total duration of the study will
      be 48 days. Fenofibric acid (FFA) PK will be determined for all 3 sampling periods and
      compared. Results from this study will inform us about a potentially clinically relevant drug
      drug interaction between fenofibrate and RTV boosted PI combinations. This information may
      therefore assist clinicians in choosing triglyceride lowering therapy for their HIV infected
      patients.
    

Intervention name(s): Fenofibrate; Ritonavir; Lopinavir/Ritonavir
Intervention type(s): Drug; Drug; Drug
Intervention MeSH terms: Ritonavir; Lopinavir; Fenofibrate
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: HIV; Hypertriglyceridemia; Protease Inhibitors; Healthy Volunteer; HV