Drug Interaction Study of Lopinavir/Ritonavir and Gemfibrozil
Condition: Healthy Volunteers
Study type: Interventional

Summary: 
      This study will determine whether the protease inhibitor lopinavir/ ritonavir (Kaletra
      (Trademark)), which is used to treat HIV disease, lowers blood levels of the lipid-regulating
      drug gemfibrozil (Lopid (Trademark)) in HIV-negative healthy volunteers. Many patients with
      HIV infection who take protease inhibitors have abnormally high lipids (cholesterol and
      triglycerides). Gemfibrozil, commonly used to treat high triglycerides, often is not
      effective in HIV-infected patients taking protease inhibitors, possibly because of an
      interaction between the two medicines that causes a lowering of gemfibrozil's levels in the
      blood. Results from this study will give researchers information on whether lopinavir/
      ritonavir affects the blood levels of gemfibrozil.

      Healthy, normal volunteers between 18 and 65 years old who test negative for HIV may be
      eligible for this study.

      On study day 1, subjects have a blood sample drawn from a catheter inserted into a vein in
      the arm to determine pre-dosing blood levels of gemfibrozil. They then take a gemfibrozil
      tablet and are given breakfast 30 minutes after taking the drug. Blood samples are obtained
      through the catheter at 0, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after dosing to determine
      gemfibrozil levels at those intervals. At the end of 12 hours, the catheter is removed and
      the subject is discharged from the clinic. The next morning subjects return to the clinic for
      another blood sample, collected through a vein in the arm.

      Subjects begin taking lopinavir/ ritonavir between 7 and 35 days after their first dose,
      depending on their schedule and the clinic schedule. On the fourteenth day of dosing subjects
      come to the clinic and are given a single dose of gemfibrozil, as on study day 1, and have
      breakfast 30 minutes later. Blood samples are collected to determine gemfibrozil levels just
      like on study days 1 and 2. An additional sample is collected for routine lab tests.
    

Detailed description: 
      Hyperlipidemia continues to be a common problem in individuals with HIV, particularly those
      receiving HIV protease inhibitors (PIs) or the nucleoside reverse transcriptase inhibitor,
      stavudine. PI-treated patients have been noted to have increases in low-density lipoprotein
      (LDL), triglycerides (TG), and total cholesterol compared to PI-treatment naive individuals.
      The prevalence of lipid abnormalities in patients receiving PI-containing therapy has been
      estimated at 27-57 percent; moreover, cardiovascular complications have begun to be revealed.
      Triglyceride elevations, in particular, are not only an independent risk factor for the
      development of coronary artery disease, but may also lead to pancreatitis. Despite treatment
      with fibric acid derivatives, such as gemfibrozil, TGs typically remain elevated above the
      upper limit of normal in HIV-infected subjects. One possible reason for persistently elevated
      TGs in these patients is reduced efficacy of their fibric acid therapy, which may result from
      an unrecognized drug-drug interaction. Fibric acid derivatives are metabolized in the liver
      via uridine 5'-diphosphate-glucuronosyl transferase enzymes (UGT), which are induced by the
      HIV PI ritonavir. Indeed, ritonavir significantly lowers plasma concentrations of other drugs
      metabolized by this enzymatic system by 40-50 percent. As UGT activity is induced, the
      metabolism of UGT substrates (gemfibrozil) will increase, resulting in a decrease in their
      plasma concentrations. Preliminary data in non-HIV-infected subjects suggest that reduced
      plasma concentrations of gemfibrozil are likely to result in reduced efficacy of the drug.
      Despite the fact that many HIV-infected patients with hypertriglyceridemia are likely to be
      receiving triglyceride-lowering therapy with a fibric acid derivative while simultaneously
      receiving antiretroviral therapy that includes ritonavir (i.e. lopinavir + ritonavir
      [LPV/r]), these two drugs have not been studied in combination to determine whether or not
      they interact. The objective of this study is to characterize the impact of LPV/r on the
      pharmacokinetic (PK) profile of gemfibrozil, after a single 600 mg oral dose, administered to
      healthy volunteers. In a longitudinal study design, fifteen subjects will receive a single,
      600 mg dose of gemfibrozil before and after 13 days of LPV/r 400/100 mg twice daily.
      Gemfibrozil pharmacokinetics will be determined on days one and 14 and compared using the
      student t-test. Results from this study will provide (or refute) the rationale for further
      studies designed to assess the possibility of dose-adjusting gemfibrozil when it is given in
      combination with ritonavir in order to maximize the pharmacologic effects of gemfibrozil.
    

Intervention name(s): Lopinavir/Ritonavir; Gemfibrozil
Intervention type(s): Drug; Drug
Intervention description(s): lopinavir 400 mg + ritonavir 100 mg twice daily for 2 weeks; Control arm (no intervention used in this arm)
Other intervention name(s): lopinavir/ritonavir = Kaletra(TM); gemfibrozil (Teva Pharmaceuticals)
Intervention MeSH terms: Ritonavir; Lopinavir; Gemfibrozil
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Keywords: Pharmacokinetic; HIV; Drug-Drug Interaction; Lopinavir/Ritonavir; Gemfibrozil; Healthy Volunteer; HV