Pharmacokinetic Interaction Study of Efavirenz and American Ginseng in Healthy Volunteers

This study is supported by R01AT005526-01 grant awarded by National Center for Complementary
and. Alternative Medicine (NCCAM) to evaluate the safety, efficacy, and mechanism of American
ginseng in HIV-related fatigue. This is a 4-week sequential drug interaction study to measure
the effects of American ginseng on efavirenz pharmacokinetics using steady-state 24-hour AUC
and Cmax as the primary comparison measures in healthy male volunteers. Efavirenz Cmin, T1/2,
tmax, and clearance will also be assessed as secondary outcome measures. This study is a
phase I, prospective, within-subject, fixed-order, two-period, multiple dose, open label,
drug interaction study, to determine the stead-state plasma pharmacokinetic profile of
efavirenz before and after concurrent treatment with American ginseng. Therefore, this study
will evaluate the effects of American ginseng on efavirenz plasma concentrations. Only
efavirenz plasma concentrations will be measured in this study. American ginseng plasma
concentrations will not be assessed in this study. Efavirenz plasma concentrations will be
measured on study Days 14 and 28 (corresponding to weeks 2 and 4, respectively).

This is an important study because although American ginseng is a popular dietary supplement,
the safety and efficacy of this agent in HIV-infected patients has not yet been established.
A major concern regarding the safety of American ginseng in HIV-infected patients is the
potential for herb-drug interactions that could alter the metabolism of antiretroviral drugs.
Induction of drug metabolizing enzymes by dietary supplements such as American ginseng, could
lead to a reduction in the therapeutic concentrations of these drugs and treatment failure.
Inhibition of these drug metabolizing enzymes, on the other hand, could result in higher
plasma concentrations of antiretroviral agents and potentially lead to increased toxicity.

Most antiretroviral drugs are metabolized by the cytochrome P450 (CYP450) isoenzyme CYP3A4.
Our preliminary data suggest that American ginseng does not significantly affect CYP3A4
activity in vivo. A recent study has also reported that the American ginseng-mediated
induction of Uridyl dipohsphate (UDP)-glucuronosyltransferase enzyme involved in the
metabolism of the nucleoside reverse transcriptase inhibitors (NRTIs) zidovudine and
abacavir, and the integrase inhibitor raltegravir, does not significantly alter zidoduvine
pharmacokinetics. However, data are not available concerning the effect of American ginseng
on other major CYP 450 isoforms involved in the metabolism of antiretroviral drugs. For
instance, the non- nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz is also
metabolized by CYP2B6 and only to a lesser extent by the CYP3A4 isoform. Therefore, a
potential drug interaction between American ginseng and this popular NNRTI must be excluded
before this herb can be safely used in HIV-infected patients. This study will complete the
work that has been currently done characterizing the effects of American ginseng on major
drug metabolizing enzymes.

DURATION:

The total duration of this study is five weeks. Participants will receive study medications
during the first four weeks of the study. On week 5 participants will complete their final
post treatment safety study visit.

POPULATION AND SAMPLE SIZE:

Fifteen adult healthy male volunteers will be enrolled in this study.

REGIMEN:

Period 1 Days 0-14 Daily efavirenz monotherapy 600 mg orally Efavirenz pharmacokinetic
sampling on Day 14

Period 2 Days 15-28 Daily efavirenz 600 mg orally PLUS American ginseng 3000 mg orally
Efavirenz pharmacokinetic sampling on Day 28

Because efavirenz is a Category D drug with positive evidence of fetal risk, only male
healthy volunteers will be enrolled in this study. Our hypothesis is that concurrent oral
administration of American ginseng for up to 14 days will not significantly alter the
steady-state plasma pharmacokinetic of efavirenz.

Inclusion Criteria:

1. All enrollees will be healthy volunteers, ≥18 years of age with

2. Negative HIV-1 serology, documented by any licensed ELISA test kit

3. Ability and willingness to provide a signed informed consent and comply with study
requirements

4. Males only because efavirenz has been reported to have teratogenic properties

5. Estimated creatinine clearance ≥50 mL/minute, as calculated by the Cockcroft-Gault
method

6. Normal laboratory and physical examination, as judged by the Principal Investigator

7. Good peripheral venous access

8. Willingness and ability to take oral medications.

Exclusion Criteria:

1. Known or suspected hypersensitivity to American Ginseng (AG) or efavirenz

2. Taking any prescription, over-the-counter medication, or Complementary and alternative
medicine (CAM) agents within 30 days of study enrolment

3. Evidence of active drug or alcohol abuse

4. Any other medical or psychological condition that might, in the opinion of the
investigator, interfere with participation in the study or put subjects at undue risk

5. Hospitalization or therapy for serious illness within 30 days prior to study entry, as
judged by the investigator

6. Participation in any investigational drug trials within 30 days prior to study entry
that, in the opinion of the investigator, would preclude study participation.