- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00878306
Disulfiram Interactions With HIV Medications: Clinical Implications
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Cocaine and alcohol abuse are strongly linked to HIV infection and transmission of the virus. Disulfiram has long been approved by the US FDA for the treatment of alcohol and recent data shows it to be effective in reducing cocaine abuse. Disulfiram and antiretroviral medications (ARV) are metabolized by cytochrome P450 3A and concomitant use of these drugs could potentially produce adverse drug interactions underscoring the need to identify and understand the clinical implications of these drug interactions in order to more effectively treat individuals with both HIV disease and cocaine and/or alcohol use disorders. This will be accomplished by conducting studies aimed at identifying whether pharmacokinetic or pharmacodynamic drug interactions of importance occur between disulfiram and medications frequently utilized in those with HIV/AIDS.
Abuse of cocaine and/or alcohol has been shown to be a significant risk factor for HIV infections as a result of high risk sexual and drug use behaviors occurring in the context of use of these substances. Those with HIV infection and untreated cocaine and/or alcohol dependence are also at a high risk of transmitting HIV to others. Moreover, those with HIV disease and substance dependence often experience poor clinical outcomes as a result of nonadherence to HIV treatment regimens.
Disulfiram (DIS) is an inhibitor of ALDH and has been reported to alter hepatic cytochrome P450 enzyme function important to metabolism of many drugs frequently used in the treatment of HIV/AIDS. Although approved for the treatment of alcohol dependence, DIS has been studied as a treatment for cocaine addiction in recent years. DIS at the standard 250 mg daily dose has been associated with significant reductions in cocaine use as well as alcohol use in those with histories of concomitant cocaine-alcohol abuse. DIS 250 mg daily has been shown to have a significant pharmacokinetic interaction with cocaine resulting in delayed cocaine clearance. In order to more fully access possible use of DIS treatment for cocaine and/or alcohol dependence in this population, it is important to determine if any excess risk is conveyed as a result of drug interactions that might occur between DIS and the ARV medications.
This study will be using a standard clinical pharmacology study design using a within-subject design examining the two drug interaction studies between DIS (250 mg daily) and the following medications:
- Non-nucleoside reverse transcriptase inhibitor, efavirenz 600 mg daily for 10 days
Protease inhibitors atazanavir 400 mg daily for 8 days or ritonavir 200 mg daily for 8 days
Additional data will be collected and analyzed including:
- Clinical data on effects of these medications alone and in combination on cardiac conduction, hepatic function, and serum lipids will be obtained
- The safety of co-administration of alcohol containing HIV preparations (ritonavir) with DIS will be determined
- The effect of ARV on DIS function as determined by ALDH activity and DIS and metabolite concentrations will be determined using a control sample within-subject design (DIS doses of 62.5 mg and 250 mg daily) and between subjects design.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
-
-
California
-
San Francisco, California, United States, 94110
- San Francisco General Hospital
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Good health and without clinical findings that require medical or psychiatric intervention as determined by a physical and mental status examination and screening laboratory tests, urinalysis, and ECG
- 18 years of age or older
- Willing to abstain from alcohol during the study and for two weeks afterward
Exclusion Criteria:
- Patients who are receiving concurrently other drugs that are inducers or inhibitors of hepatic microsomal enzymes
- Patients with a known sensitivity to the HIV therapeutics to be studied
- Pregnant or nursing mothers
- Current major affective or psychotic illnesses or suicidality
- Clinically active hepatitis
- Diabetes, hyperlipidemia, coagulation disorders, or renal disease will be excluded
- Those meeting criteria for current alcohol or drug dependence (other than nicotine)
- HIV infection
Study Plan
How is the study designed?
Design Details
- Allocation: Randomized
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: Disulfiram
|
62.5 mg daily x3 days, then 250 mg daily x3 days
Other Names:
|
Experimental: Disulfiram + Efavirenz
Efavirenz alone, then in addition with Disulfiram
|
Efavirenz 600 mg daily x10 days, then in addition with 62.5 mg daily x3 days, then Disulfiram 250 mg daily x3 days
|
Experimental: Disulfiram + Atazanavir
Atazanavir alone, then in addition with Disulfiram
|
Atazanavir 400 mg daily x8 days, then in addition with 62.5 mg daily x3 days, then Disulfiram 250 mg daily x3 days
|
Experimental: Disulfiram + Ritonavir
Ritonavir alone, then in addition with Disulfiram
|
Ritonavir 200 mg daily x8 days, then in addition with 62.5 mg daily x3 days, then Disulfiram 250 mg daily x3 days
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
The effect of disulfiram on the pharmacokinetics of each of the antiretroviral medications to be studied
Time Frame: Measured at Day 15
|
Measured at Day 15
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
The effect of the antiretroviral medications on disulfiram measured by ALDH activity and disulfiram pharmacokinetics
Time Frame: Measured at Day 0, Day 4, and Day 8
|
Measured at Day 0, Day 4, and Day 8
|
Cardiac Conduction
Time Frame: Measured at screening and during pharmacokinetic studies
|
Measured at screening and during pharmacokinetic studies
|
Hepatic Function
Time Frame: Measured at screening and during pharmacokinetic studies
|
Measured at screening and during pharmacokinetic studies
|
Serum Lipids
Time Frame: Measured at screening and during pharmacokinetic studies
|
Measured at screening and during pharmacokinetic studies
|
Safety of co-administration of alcohol containing HIV preparations (ritonavir) and Disulfiram
Time Frame: Measured at day 11- day 15
|
Measured at day 11- day 15
|
Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Elinore F McCance-Katz, M.D., Ph.D, University of California, San Francisco
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Mental Disorders
- Chemically-Induced Disorders
- Substance-Related Disorders
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Antiviral Agents
- Reverse Transcriptase Inhibitors
- Nucleic Acid Synthesis Inhibitors
- Enzyme Inhibitors
- Anti-HIV Agents
- Anti-Retroviral Agents
- Protease Inhibitors
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Enzyme Inducers
- Cytochrome P-450 CYP3A Inducers
- Alcohol Deterrents
- HIV Protease Inhibitors
- Viral Protease Inhibitors
- Cytochrome P-450 CYP2B6 Inducers
- Cytochrome P-450 CYP2C9 Inhibitors
- Cytochrome P-450 CYP2C19 Inhibitors
- Acetaldehyde Dehydrogenase Inhibitors
- Ritonavir
- Atazanavir Sulfate
- Efavirenz
- Disulfiram
Other Study ID Numbers
- R01DA024982 (U.S. NIH Grant/Contract)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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