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
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
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
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 combination lopinavir/ritonavir (LPV/r). Secondary objectives
will assess the influence of E. purpurea, G. biloba, and P. ginseng on (1) CYP3A enzyme
activity and (2) P-gp mediated drug transport. 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 receive single oral doses of fexofenadine 120 mg and midazolam 8 mg followed
by plasma collection for determination of baseline CYP3A and P-gp phenotypes (Study Day 1).
Between 7 and 28 days after Day 1, subjects will begin taking LPV/r (400mg/100mg twice daily
x 29.5 days), returning to the NIH on Day 15 of LPV/r 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 and ritonavir
concentrations. On the last day (28th day) of herbal supplementation, participants will
return to the NIH for determination of P-gp and 3A phenotypes using single doses of
fexofenadine and midazolam as described for Study Day 1. Data from this investigation will
determine whether echinacea, ginseng, or ginkgo biloba supplements alter the
pharmacokinetics of the protease inhibitor combination lopinavir/ritonavir, and whether or
not modulation of CYP3A and/or P-gp contributed to any observed interaction.
- 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 fexofenadine administration
and 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.
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
- 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
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
9. History of intolerance or allergic reaction to lopinavir, ritonavir, midazolam, or
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