The Effect of Milk Thistle on the Pharmacokinetics of Indinavir

This study has been completed.
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00011635
First received: February 24, 2001
Last updated: March 3, 2008
Last verified: December 2000
  Purpose

Complementary and alternative medicines are widely used in the HIV-infected population. Recent data have shown serious drug interactions between certain complementary medicines and protease inhibitors. Silymarin (Milk thistle) is a commonly used dietary supplement in HIV-infected patients for treatment of hepatitis or as a hepato-protectant. Data are available suggesting that it may alter cytochrome P4503A4-mediated drug metabolism. To evaluate the effect of milk thistle on the protease inhibitor, indinavir (IDV), ten healthy subjects will receive IDV (Crixivan) alone and in combination with an over-the-counter silymarin preparation. IDV will initially be administered alone at a dose of 800 mg Q8H for four doses and serial samples will be collected for determination of IDV pharmacokinetics after the morning dose on day 2. Subjects will then initiate therapy will milk thistle using a standardized formulation and dose for three weeks after which subjects will then again take 4 doses of IDV and have serial samples collected for IDV plasma concentrations. There will then be a 11-day washout period with no drugs, after which IDV will again be given for 4 doses and samples will be collected evaluate the offset of the effects of milk thistle. To examine the effect of milk thistle on other CYP450 pathways, subjects will receive a single dose of caffeine and dextromethorphan and have urine collected before and after milk thistle, and after the washout period. Indinavir, caffeine, and dextromethorphan concentrations in plasma or urine will be determined using validated HPLC methods. Steady-state noncompartmental parameters of indinavir in the presence and absence of milk thistle will be determined. Pharmacokinetic parameters will be compared using ANOVA that will include factors for a period effect and a treatment effect. Statistical analyses will include calculation of the mean ratio of the AUC in the treatment phases compared to IDV alone and determination of 95% confidence intervals. This study will help define the drug interaction potential of complementary and alternative therapies in HIV-infected patients.


Condition Intervention Phase
HIV Infection
Healthy
Drug: Silymarin (milk thistle)
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Primary Purpose: Treatment
Official Title: The Effect of Milk Thistle on the Pharmacokinetics of Indinavir

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Estimated Enrollment: 20
Study Start Date: February 2001
Estimated Study Completion Date: June 2001
Detailed Description:

Complementary and alternative medicines are widely used in the HIV-infected population. Recent data have shown serious drug interactions between certain complementary medicines and protease inhibitors. Silymarin (Milk thistle) is a commonly used dietary supplement in HIV-infected patients for treatment of hepatitis or as a hepato-protectant. Data are available suggesting that it may alter cytochrome P4503A4-mediated drug metabolism. To evaluate the effect of milk thistle on the protease inhibitor, indinavir (IDV), ten healthy subjects will receive IDV (Crixivan) alone and in combination with an over-the-counter silymarin preparation. IDV will initially be administered alone at a dose of 800 mg Q8H for four doses and serial samples will be collected for determination of IDV pharmacokinetics after the morning dose on day 2. Subjects will then initiate therapy will milk thistle using a standardized formulation and dose for three weeks after which subjects will then again take 4 doses of IDV and have serial samples collected for IDV plasma concentrations. There will then be an 11-day washout period with no drugs, after which IDV will again be given for 4 doses and samples will be collected evaluate the offset of the effects of milk thistle. To examine the effect of milk thistle on other CYP450 pathways, subjects will receive a single dose of caffeine and dextromethorphan and have urine collected before and after milk thistle, and after the washout period. Indinavir, caffeine, and dextromethorphan concentrations in plasma or urine will be determined using validated HPLC methods. Steady-state noncompartmental parameters of indinavir in the presence and absence of milk thistle will be determined. Pharmacokinetic parameters will be compared using ANOVA that will include factors for a period effect and a treatment effect. Statistical analyses will include calculation of the mean ratio of the AUC in the treatment phases compared to IDV alone and determination of 95% confidence intervals. This study will help define the drug interaction potential of complementary and alternative therapies in HIV-infected patients.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Age 18 to 65 years.

Healthy by medical history and physical exam.

No concurrent chronic medications, including oral contraceptives.

Non-smoker or not having smoked for the past 6 months or longer.

Laboratory values within established NIAID guidelines for participation in clinical studies: AST/SGOT less than or equal to 2 times ULN; Serum creatinine less then or equal to ULN; Hemoglobin greater than or equal to 10 g/dl.

Ability to abstain from caffeine containing foods/beverages, ethanol, grapefruit or grapefruit juice and charbroiled foods for 72 hours prior to, and the day of, phenotyping procedures.

Ability to abstain from dextromethorphan-containing over the counter preparations for 72 hours prior to, and the day of, phenotyping procedures.

No concomitant therapy with other inhibitors or inducers of cytochrome P-450 mediated drug metabolism within 30 days of study (including grapefruit juice).

No ingestion of dietary supplements within the past 30 days.

Ability to obtain venous access for sample collection.

No presence of life-threatening or unstable renal, hepatic, cardiovascular, hematologic, neurologic, psychiatric, or respiratory disease or any other condition that may interfere with the interpretation of the study results or not be in the best interests of the patient in the opinion of the investigator.

Patients must not have a positive pregnancy test.

No presence of persistent diarrhea or malabsorption that would interfere with the patient's ability to adequately absorb drugs.

No drug or alcohol use that may impair safety or adherence.

No history of intolerance to milk thistle, indinavir, caffeine, or dextromethorphan preparations.

  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: NCT00011635

Locations
United States, Maryland
Warren G. Magnuson Clinical Center (CC)
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
  More Information

Publications:
ClinicalTrials.gov Identifier: NCT00011635     History of Changes
Other Study ID Numbers: 010054, 01-CC-0054
Study First Received: February 24, 2001
Last Updated: March 3, 2008
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Caffeine
Cytochrome P 450
Dextromethorphan
Drug Interaction
Metabolism
Drug Metabolism
Healthy Volunteer
Milk Thistle

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Silymarin
Indinavir
Antioxidants
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protective Agents
Physiological Effects of Drugs
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 24, 2014