Pharmacokinetic Interaction Study of Efavirenz and American Ginseng in Healthy Volunteers

The recruitment status of this study is unknown because the information has not been verified recently.
Verified June 2010 by Johns Hopkins University.
Recruitment status was  Active, not recruiting
Sponsor:
Collaborator:
Information provided by:
Johns Hopkins University
ClinicalTrials.gov Identifier:
NCT01136928
First received: June 2, 2010
Last updated: May 9, 2011
Last verified: June 2010
  Purpose

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. The investigators 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.


Condition Intervention Phase
Healthy Volunteers
Drug: American ginseng
Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Official Title: Phase I Pharmacokinetic Interaction Study of Efavirenz and American Ginseng in Healthy Volunteers

Resource links provided by NLM:


Further study details as provided by Johns Hopkins University:

Primary Outcome Measures:
  • To compare efavirenz AUC0-24 and Cmax when dosed alone to steady-state efavirenz AUC0-24 and Cmax given concurrently with American ginseng. Efavirenz AUC0-24 with and without American ginseng [ Time Frame: 14 days of efavirenz alone, followed by 14 days of concurrent administration of efavirenz and American ginseng ] [ Designated as safety issue: Yes ]
    Compare efavirenz AUC0-24 and Cmax when dosed alone at 600 mg daily, to steady-state efavirenz AUC0-24 and Cmax dosed at 600 mg daily and given concurrently with American ginseng 3000 mg daily.


Secondary Outcome Measures:
  • Efavirenz tmax with and without American ginseng [ Time Frame: 14 days of efavirenz alone, followed by 14 days of concurrent administration of efavirenz and American ginseng ] [ Designated as safety issue: Yes ]
    To compare efavirenz tmax at steady-state when dosed alone as 600 mg daily, to steady-state efavirenz tmax dosed at 600 mg daily and given concurrently with American ginseng 3000 mg daily in HIV-seronegative healthy male volunteers.

  • Efavirenz Cmin with and without American ginseng [ Time Frame: 14 days of efavirenz alone, followed by 14 days of concurrent administration of efavirenz and American ginseng ] [ Designated as safety issue: Yes ]
    To compare efavirenz Cmin at steady-state when dosed alone as 600 mg daily, to steady-state efavirenz Cmin dosed at 600 mg daily and given concurrently with American ginseng 3000 mg daily in HIV-seronegative healthy male volunteers.

  • Efavirenz Clearance with and without American ginseng [ Time Frame: 14 days of efavirenz alone, followed by 14 days of concurrent administration of efavirenz and American ginseng ] [ Designated as safety issue: Yes ]
    To compare efavirenz Clearance at steady-state when dosed alone as 600 mg daily, to steady-state efavirenz Clearance dosed at 600 mg daily and given concurrently with American ginseng 3000 mg daily in HIV-seronegative healthy male volunteers

  • Efavirenz T1/2 with and without American ginseng [ Time Frame: 14 days of efavirenz alone, followed by 14 days of concurrent administration of efavirenz and American ginseng ] [ Designated as safety issue: Yes ]
    To compare efavirenz T1/2 at steady-state when dosed alone as 600 mg daily, to steady-state efavirenz T1/2 dosed at 600 mg daily and given concurrently with American ginseng 3000 mg daily in HIV-seronegative healthy male volunteers


Estimated Enrollment: 15
Study Start Date: July 2010
Estimated Study Completion Date: July 2011
Estimated Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: American ginseng and efavirenz
This is a sequential study. Healthy volunteers will receive efavirenz alone for 14 days followed by efavirenz plus American ginseng for an additional 14 days.
Drug: American ginseng
Healthy volunteers will ge given efavirnez 600 mg daily monotherapy for 14 days followed by efavirenz 600 mg PLUS American ginseng 3000 mg daily for an additional 14 days.
Other Names:
  • Efavienz (Sustiva)
  • American ginseng

  Hide Detailed Description

Detailed Description:

This study is supported by R01AT005526-01 grant awarded by 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 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

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 AG or efavirenz
  2. Taking any prescription, over-the-counter medication, or 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01136928

Locations
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21287-5554
Sponsors and Collaborators
Johns Hopkins University
Investigators
Principal Investigator: Adriana Andrade, MD, MPH Johns Hopkins University
  More Information

No publications provided

Responsible Party: Sheila A. Caldwell, Ph.D., National Center for Complementary and Alternative Medicine
ClinicalTrials.gov Identifier: NCT01136928     History of Changes
Other Study ID Numbers: NA_00038067, R01AT005526-01
Study First Received: June 2, 2010
Last Updated: May 9, 2011
Health Authority: United States: Institutional Review Board

Keywords provided by Johns Hopkins University:
Antiretroviral therapy
American ginseng
Efavirenz
Cytochrome P450 enzymes
Complementary and Alternative Medicine
Herbal
Pharmacikinetics
Healthy volunteers

Additional relevant MeSH terms:
Efavirenz
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Anti-HIV Agents

ClinicalTrials.gov processed this record on July 22, 2014