Drug Interactions of Echinacea, Ginseng, and Ginkgo Biloba Taken With Lopinavir/Ritonavir in Healthy Volunteers
Condition: Healthy
Study type: Interventional
Phase: Phase 4

Summary: 
      This study will examine the interaction of the HIV combination medication lopinavir/ritonavir
      with the herbal products echinacea, ginseng, and ginkgo biloba. Patients with HIV infection
      often take herbal products and dietary supplements in addition to their doctor-prescribed
      medicines to treat the disease, lessen the side effects of anti-viral drugs, and improve
      their overall well being. Alternative medicines such as these may, however, interfere with
      the elimination of lopinavir/ritonavir from the body, causing either higher or lower blood
      levels of these drugs than would be expected. This study will assess in healthy subjects any
      potential harms of taking echinacea, ginseng, or ginkgo biloba together with
      lopinavir/ritonavir.

      Healthy normal volunteers between 18 and 50 years of age may be eligible for this study.
      Candidates are screened with a history, physical examination, and blood tests, including an
      HIV test and a pregnancy test for women. Pregnant women are excluded from the study.
      Participants come to the NIH Clinical Center after fasting overnight for the following
      procedures:

      Visits 1 and 2: A catheter (plastic tube) is placed in an arm vein to collect blood samples.
      After the first sample is drawn, the subject takes 8 mg of midazolam syrup and two
      fexofenadine tablets. Midazolam is a sedative, and fexofenadine (Allegra) is a medicine used
      to treat allergies. Subjects are given breakfast an hour after taking the drugs. Blood
      samples are collected at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8 and 24 hours after taking
      the drugs to measure blood levels of fexofenadine. An extra sample is collected at the 4-hour
      mark to measure the midazolam level. The catheter is removed after the 8-hour blood draw and
      subjects are dismissed home. They return the following morning (visit 2) for the 24-hour
      blood draw.

      Visit 3: From 7 to 28 days after visit 1, subjects begin taking lopinavir/ritonavir capsules
      twice a day by mouth for a total of 29.5 days. On day 15 they return to the clinic for
      lopinavir/ritonavir blood levels as were done for fexofenadine, except that samples are
      collected once before breakfast and then at 0.5, 1, 2, 3, 4, 6, 8 and 12 hours after the
      lopinavir/ritonavir dose. An extra sample is collected for routine tests. The catheter is
      removed after the 12-hour draw and the subject is dismissed home.

      The next morning, subjects begin taking one of the following: echinacea 500 mg 3 times a day;
      ginkgo biloba 120 mg twice a day; or ginseng 500 mg 3 times a day for 28 days.

      Visit 4: On the last day of taking lopinavir/ritonavir, subjects return to the clinic again
      for blood level measurements of these drugs as on visit 3, except that the catheter is
      removed and the subject dismissed home after the 8-hour blood draw.

      Visits 5 and 6: On the last day of taking the herbal supplement, subjects return to the
      clinic for repeat measurement of fexofenadine and midazolam levels, as described in visits 1
      and 2. At the final visit (visit 6) an additional blood sample is collected for repeat
      laboratory testing.

      ...
    

Detailed description: 
      Patients with HIV commonly use herbal products and dietary supplements in addition to
      medications prescribed by their physicians. Up to 73% of patients with HIV have reported
      using some form of complementary or alternative medicine. As such, the potential for
      clinically significant drug interactions between herbs and antiretrovirals is becoming
      increasingly appreciated. Despite this awareness, little is known about the effect of
      commonly used herbal products, such as echinacea, ginkgo biloba, and ginseng, on
      antiretroviral pharmacokinetics. Interacting herbal supplements have the potential to alter
      protease inhibitor (PI) plasma concentrations, as has been shown with St. John's Wort and
      garlic. Drug interactions may potentially increase antiretroviral concentrations, putting
      patients at risk for toxicities, or lower drug concentrations below the threshold of viral
      susceptibility, putting patients in jeopardy of antiretroviral failure. The protease
      inhibitors lopinavir and ritonavir both rely principally on cytochrome P450 (CYP) 3A4
      metabolism for their elimination. In addition, both drugs are substrates for the transport
      protein p-glycoprotein (P-gp), which may also contribute to their distribution and
      elimination.

      The primary purpose of this investigation is to determine whether the herbal supplements
      Echinacea purpurea, ginkgo biloba, and Panax ginseng alter the pharmacokinetic properties of
      the HIV protease inhibitor (PI) lopinavir, administered as the PI combination
      lopinavir/ritonavir (LPV/r). This is an open label pharmacokinetic study that will be
      performed on an outpatient basis. A total of 42 study participants who have met inclusion
      criteria will be sequentially divided into one of 3 groups, such that 14 subjects each will
      receive LPV/r alone and in combination with either E. purpurea, G. biloba, or P. ginseng.

      Subjects will begin taking LPV/r (400mg/100mg twice daily x 29.5 days), returning to the NIH
      on Day 15 of dosing for post-dose plasma collection and determination of lopinavir and
      ritonavir concentrations. On Day 16 participants will begin taking either E. purpurea (500mg,
      three times daily), G. biloba extract (120 mg, twice daily), or P. ginseng (500 mg, twice
      daily) for 28 days. On the 30th day of LPV/r (Day 15 of the herb), subjects will return to
      the NIH where they will take their final LPV/r dose and then have their plasma collected for
      determination of lopinavir concentrations. Data from this investigation will determine
      whether echinacea, ginseng, or ginkgo biloba supplements alter the pharmacokinetics of
      lopinavir.
    

Intervention name(s): Gingko Biloba; Echinacea purpurea; Panax ginseng
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Ginkgo Biloba 120 mg twice daily for 14 days; Echinacea purpurea 500 mg three times daily for 14 days; Panax ginseng 500 mg twice daily
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Keywords: Antiretrovirals; Protease Inhibitors; Herbal Supplements; Drug Interactions; Metabolism; Healthy Volunteer; HV