Drug Interactions of Echinacea, Ginseng, and Ginkgo Biloba Taken With Lopinavir/Ritonavir in Healthy Volunteers
Condition: Healthy
Intervention: Gingko Biloba; Echinacea purpurea; Panax ginseng
Intervention description: 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
Phase: Phase 4
Study type: Interventional
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 47.0
Sex: All
Minimum age: 18 Years
Maximum age: 50 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Antiretrovirals; Protease Inhibitors; Herbal Supplements; Drug Interactions; Metabolism; Healthy Volunteer; HV

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.

      ...
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

               1. Males and females between the ages of 18 and 50 years.

               2. Healthy by medical history and physical exam.

               3. Laboratory values within established guidelines for participation in clinical
                  studies: AST less than or equal to 2 times the ULN; SCr less than or equal to
                  ULN; hemoglobin equal to or greater than 11 g/dL (for both males and females).

               4. Ability to abstain from ingesting fruit juice during pharmacokinetic sampling
                  periods (a total of 2 study days), and abstain from eating grapefruit or drinking
                  grapefruit juice during the entire study period.

               5. Negative serum or urine pregnancy test for females of child-bearing potential.

               6. Females of child-bearing potential who are able and willing to practice
                  abstinence or use non-hormonal effective methods of birth control during the
                  study, such as condoms or diaphragms.

        EXCLUSION CRITERIA:

          1. Concomitant routine therapy with any prescription, over-the-counter, herbal, or
             holistic medications, including oral contraceptives, for 30 days prior to study
             participation. Intermittent use of any medication within 30 days prior to screening
             will be considered case by case by the principal investigator and the medically
             accountable investigator.

               -  Concomitant therapy (chronic or intermittent) with any prescription,
                  over-the-counter, or herbal drugs (including tinctures, foods, beverages, and
                  gum) will not be allowed during the study duration, including any intermittent
                  use of allergy medication.

               -  Intermittent use of acetaminophen, non-steroidal anti-inflammatory medications
                  (i.e. ibuprofen), and loperamide will be allowed during the study, but should not
                  be taken on the days of pharmacokinetic blood sampling.

               -  A daily multivitamin with minerals will be allowed during the study.

          2. Inability to obtain venous access for blood sample collection.

          3. The presence or history of any of the following: diabetes mellitus (clinical diagnosis
             based on current guidelines, HIV infection, active tuberculosis, cardiac disease (eg.
             Hypertension [SBP greater than 140 mmHG or DBP greater than 90 mmHG], heart failure,
             arrhythmia, etc.), renal disease, hepatitis or hepatic impairment, pancreatitis,
             bleeding disorders, internal bleeding (such as gastrointestinal or intracranial),
             respiratory disease (eg. asthma requiring maintenance pharmacologic therapy, chronic
             obstructive pulmonary disease, etc.), peptic ulcer disease, osteoporosis,
             osteonecrosis, atopy or atopic dermatitis, hormone sensitive cancers or conditions,
             organ transplant, seizure disorders, schizophrenia or other psychiatric illnesses that
             may interfere with the subject's ability to participate in the study, or any other
             condition that may interfere with the interpretation of the study results or not be in
             the best interest of the subject in the opinion of the investigators.

          4. Plans for elective surgery during the investigation or within 1 month following
             completion for subjects in the gingko biloba arm of the study.

          5. Positive serum or urine pregnancy test or breastfeeding female.

          6. The presence of persistent diarrhea or malabsorption that would interfere with the
             subject's ability to absorb drugs.

          7. Drug or alcohol abuse that may impair safety or adherence (more than 3 alcoholic
             drinks per day, on a daily basis).

          8. History of intolerance or allergic reaction to any products containing echinacea,
             ginkgo biloba extract, or ginseng (including pills, tinctures, foods, beverages, and
             gum).

          9. History of intolerance or allergic reaction to lopinavir, ritonavir, midazolam, or
             fexofenadine.

         10. History of atopy including atopic dermatitis, bronchial asthma, multiple food
             allergies, or severe recurring allergic rhinitis.

         11. Fasting total cholesterol greater than 240 mg/dL or fasting triglycerides greater than
             400 mg/dL.

         12. Use of nicotine-containing tobacco products, including cigarettes and chewing tobacco.