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.

Treatment or Intervention	Phase
Drug: Fexofenadine  Drug: Midazolam	Phase IV

Further Study Details: 

Expected Total Enrollment:  150

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 both 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 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 clinic 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, three times daily) for 28 days. On the 30th day of LPV/r (Day 15 of the herb), subjects will return to clinic 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 clinic 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.

Genders Eligible for Study:  Both

Accepts Healthy Volunteers

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 2x ULN; SCr less than or equal to ULN; hemoglobin equal to or greater than 11 g/dL (for both males and females).
5.) 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.
6.) Negative serum pregnancy test for females of child-bearing potential.
7.) 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.
- 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 (as assessed by patient interview), cardiac disease (eg. Hypertension [SBP greater than 140 mmHG or DBP greater than 90 mmHG], heart failure, arrhythmia, etc.), renal disease (chronic or acute renal failure or insufficiency), hepatitis (as assessed by patient interview) or hepatic impairment, pancreatitis, bleeding disorders (eg. hemophilia), internal bleeding (such as gastrointestinal or intracranial), respiratory disease (eg. asthma requiring maintenance pharmacologic therapy, chronic obstructive pulmonary disease, etc.), peptic ulcer disease requiring maintenance pharmacologic therapy, 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.
5.) Positive 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.) Prior participation in one of the study groups (enrolled or completed).

Maryland
      Warren G. Magnuson Clinical Center (CC), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  050082; 05-CC-0082
Record last reviewed:  January 6, 2005
Last Updated:  March 11, 2005
Record first received:  February 5, 2005
ClinicalTrials.gov Identifier:  NCT00103012
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08