Drug InteractionsPhase 1NCT01708369
Alcohol Inhibits Drug Metabolism by Carboxylesterases
A Phase 1 study testing Ethanol, Oseltamivir and Aspirin in people with Drug Interactions, run by University of Tennessee at 1 site in United States.
Trial summary
The purpose of this study is to determine if alcohol is able the affect the body's ability to eliminate two commonly used medication, oseltamivir and aspirin. We hypothesize that drinking alcohol may reduce the body's ability to break down these two medications along with many others.This could affect the amount of… Read more about this study
- Who is it for?
- Ages 21 to 45 yearsHealthy volunteers can take part
- Conditions the study is for
- Drug Interactions
- What is being tested?
- Ethanol, Oseltamivir and Aspirin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 19 participants
- Where
- 1 siteUnited States
- Study dates
- Feb 2012to May 2012
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 45 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Healthy volunteers ages 21-45 with no chronic medical or psychiatric conditions
- social ethanol drinker
Who cannot join
- allergy or hypersensitivity to oseltamivir or aspirin
- concomitant medication treatment (either prescription, over the counter, herbals, or supplements such as vitamins
- co-existing diseases affecting cardiovascular, hepatic, renal, pulmonary, hematologic, or gastrointestinal function
- platelet count < 100,000, hematocrit < 30
- chronic psychiatric disorder
- score >2 on the Michigan Alcohol Screening Test (MAST)
Show all 10Show fewer
- naive to alcohol ingestion, have a family history of alcohol dependence, or history of adverse responses to alcohol
- women with known pregnancy, lactation, or not using and effective method of birth control (subjects taking oral contraceptives will be excluded)
- ingestion of alcohol or caffeine during the study
- participation in another drug study or blood donation within the preceding weeks.
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Tennessee Health Science Center
Memphis, Tennessee, 38163
About this study
Official title: Inhibition of Carboxylesterase Metabolism by Ethanol
The purpose of this study is to determine if alcohol is able the affect the body's ability to eliminate two commonly used medication, oseltamivir and aspirin. We hypothesize that drinking alcohol may reduce the body's ability to break down these two medications along with many others.This could affect the amount of drug in the blood which could impact how well these drugs work and whether patients have side effects.
Read the detailed description
Carboxylesterases are enzymes that metabolize a growing number of commonly used medications. In humans, two carboxylesterases, carboxylesterase-1 (hCE1) and carboxylesterase-2 (hCE2), found primarily in the liver and intestine respectively, play an important role in the biotransformation of numerous classes of commonly used drugs containing ester groups including ACE inhibitors, anticancer agents, opiate analgesics, HMG-CoA reductase inhibitors (statins), CNS stimulants, antiviral medications, and antiplatelet agents.
Factors affecting the activity of carboxylesterases would be expected to markedly alter the pharmacokinetics and clinical effects of substrate drugs. One key factor that could affect catalytic activity is drug interactions that inhibit carboxylesterase function. The importance of inhibition of drug metabolism in medication safety and efficacy is well established for drugs that undergo metabolism by cytochrome P450 enzymes. In distinct contrast, little is known about the potential for carboxylesterases to serve as a target for metabolic inhibition mediated by drug interactions.
It is well established that ethanol is an inhibitor of cocaine metabolism, a drug that is eliminated by carboxylesterase hydrolysis. We propose that the ethanol-mediated inhibition of carboxylesterases activity demonstrated with cocaine metabolism will occur with other substrate drugs. This has widespread implications because of the large number of drugs that are carboxylesterase substrates. In the United States, over 100 million people consume ethanol making co-ingestion with carboxylesterase substrate drugs a common occurrence. We believe that this is a prevalent drug interaction that is largely overlooked and has not been systematically evaluated, but may importantly affect the disposition, safety, and efficacy of these medications. To address this gap, we will evaluate the effect of ethanol on the disposition of oseltamivir, an hCE1 substrate, and aspirin, an hCE2 substrate, in humans.
Normal healthy volunteers will report to the University of Tennessee Health Science Center Clinical Research Center (CRC) for a 10 hour stay on four separate days and receive each of the following treatments in random order:
- Oseltamivir (Tamiflu®) 150 mg. Subjects will drink orange juice (about 10 ounces although the amount may vary slightly based on weight) over 15 minutes. Fifteen minutes after drinking the orange juice, subjects will receive two (2) 75 mg capsules of oseltamivir with 5 ounces of water. Blood samples (1 teaspoonful) to determine the amount of oseltamivir in blood will be collected before the dose and 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10, and 24 hours hours after the dose. Subjects will be allowed to leave the CRC after the 10 hour blood sample is collected and return the following day for the 24 hour sample.
- Oseltamivir (Tamiflu®) 150 mg + Ethanol. In this phase, subjects will drink the same amount of orange juice over 15 minutes that will now have ethanol (alcohol) added. The amount of ethanol that will be added is calculated to achieve a blood alcohol concentration of 0.08 g/dl, which is considered to be legally intoxicated. Fifteen minutes after drinking the orange juice + ethanol, subjects will receive two (2) 75 mg capsules of oseltamivir with 5 ounces of water. Blood samples will be collected at the same times as above. An additional blood sample (1 teaspoonful) for determining the blood alcohol concentration will be collected 30 minutes after drinking the orange juice + ethanol.
- Aspirin 650 mg. Subjects will drink orange juice (about 10 ounces although the amount may vary slightly based on your weight) over 15 minutes. Fifteen minutes after drinking the orange juice, they will take two (2) 325 mg aspirin tablets with 5 oz of water. Blood samples to determine the amount of aspirin in the blood will be collected before the aspirin dose and at 10, 20, and 30 minutes after the dose and at 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 7.0, and 8.0 hours after the dose.
- Aspirin 650 mg + Ethanol. In this phase, subjects will drink the same amount of orange juice over 15 minutes that will now have ethanol (alcohol) added. The amount of ethanol that will be added is calculated to achieve a blood alcohol concentration of 0.08 g/dl, which is considered to be legally intoxicated. Fifteen minutes after drinking the orange juice + ethanol, subjects will take two (2) 325 mg aspirin tablets with 5 ounces of water. Blood samples (1 teaspoonful) to determine the amount of aspirin in the blood will be collected before the aspirin dose and at 10, 20, and 30 minutes after the dose and at 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 7.0, and 8.0 hours after the dose.
- Conditions
- Drug Interactions
- Being tested
- Placebo, Ethanol, Oseltamivir, Aspirin
- Keywords
- human carboxylesterase-1, human carboxylesterase-2, alcohol, pharmacokinetics
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PlaceboDrug
Also called Tropicana orange juice
Orange juice administered 15 minutes before subjects take oseltamivir or aspirin
EthanolDrug
Also called Ethanol plus Tropicana orange juice
Ethanol will be mixed with orange juice and subjects will drink the mixture 15 minutes before receiving oseltamivir or aspirin
OseltamivirDrug
Also called Tamiflu
Oseltamivir 150 mg orally
AspirinDrug
Aspirin 650 mg orally will be given
| Study group | Role | What they receive |
|---|---|---|
| Oseltamivir & Placebo | Active comparator | Oseltamivir 150 mg orally will be administered 15 minutes after subjects consume orange juice Receives: Drug: Placebo; Drug: Oseltamivir |
| Oseltamivir & Ethanol | Experimental | Oseltamivir 150 mg and ethanol targeted to blood alcohol concentration 0.08 g/dl Receives: Drug: Ethanol; Drug: Oseltamivir |
| Aspirin & Placebo | Active comparator | Aspirin 650 mg orally will be administered 15 minutes after subjects consume orange juice Receives: Drug: Placebo; Drug: Aspirin |
| Aspirin & Ethanol | Experimental | Aspirin 650 mg and ethanol targeted to blood alcohol concentration 0.08 g/dl Receives: Drug: Ethanol; Drug: Aspirin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Area under the plasma concentration-time curve
For determining if ethanol inhibits hCE1 or hCE2, the primary pharmacokinetic parameter of interest will be the area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) for oseltamivir phosphate and acetylsalicylic acid, respectively. Other pharmacokinetic parameters that will be characterized are maximum plasma concentration (Cmax), time to reach the maximum plasma concentration (tmax), and the elimination rate constant λz. This same pharmacokinetic analysis will also be applied to the oseltamivir carboxylate and salicylic acid metabolites. The change in the metabolite formation clearance (∆Clf) for each agent will be calculated as the ratio of the metabolite to parent AUC0-∞ when given with ethanol (inh) and alone (con) as follows: ΔClf = [AUCm/AUCp]inh/[AUCm/AUCp]con
Measured: Oseltamivir 0-24 hrs; Aspirin 0-8 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Oct 2012 (estimated)
- Study startFeb 2012
- Primary completionMay 2012
- Study completionMay 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Drug InteractionsStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 19 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Tennessee
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Robbie Parker, University of Tennessee
- Investigators
- Robert B Parker, PharmD, Principal investigator, University of TennesseeSteven C Laizure, PharmD, Principal investigator, University of Tennessee
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01708369
- Sponsor's protocol ID
- R15GM096074
- Status last verified
- Oct 2012
- First submitted
- 13 Oct 2012
- Last updated
- 16 Oct 2012
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 16 Oct 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Inhibition of Carboxylesterase Metabolism by Ethanol
- ClinicalTrials.gov ID
- NCT01708369
- Acronym / sponsor ID
- R15GM096074
- Conditions
- Drug Interactions
- Keywords
- human carboxylesterase-1, human carboxylesterase-2, alcohol, pharmacokinetics
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 19 participants (actual)
- Lead sponsor
- University of TennesseeUniversity, hospital or other
- Study start
- Feb 2012
- Primary completion
- May 2012 (actual)
- Study completion
- May 2012 (actual)
- First posted
- 16 Oct 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to determine if alcohol is able the affect the body's ability to eliminate two commonly used medication, oseltamivir and aspirin. We hypothesize that drinking alcohol may reduce the body's ability to break down these two medications along with many others.This could affect the amount of drug in the blood which could impact how well these drugs work and whether patients have side effects.
Detailed description
Carboxylesterases are enzymes that metabolize a growing number of commonly used medications. In humans, two carboxylesterases, carboxylesterase-1 (hCE1) and carboxylesterase-2 (hCE2), found primarily in the liver and intestine respectively, play an important role in the biotransformation of numerous classes of commonly used drugs containing ester groups including ACE inhibitors, anticancer agents, opiate analgesics, HMG-CoA reductase inhibitors (statins), CNS stimulants, antiviral medications, and antiplatelet agents.
Factors affecting the activity of carboxylesterases would be expected to markedly alter the pharmacokinetics and clinical effects of substrate drugs. One key factor that could affect catalytic activity is drug interactions that inhibit carboxylesterase function. The importance of inhibition of drug metabolism in medication safety and efficacy is well established for drugs that undergo metabolism by cytochrome P450 enzymes. In distinct contrast, little is known about the potential for carboxylesterases to serve as a target for metabolic inhibition mediated by drug interactions.
It is well established that ethanol is an inhibitor of cocaine metabolism, a drug that is eliminated by carboxylesterase hydrolysis. We propose that the ethanol-mediated inhibition of carboxylesterases activity demonstrated with cocaine metabolism will occur with other substrate drugs. This has widespread implications because of the large number of drugs that are carboxylesterase substrates. In the United States, over 100 million people consume ethanol making co-ingestion with carboxylesterase substrate drugs a common occurrence. We believe that this is a prevalent drug interaction that is largely overlooked and has not been systematically evaluated, but may importantly affect the disposition, safety, and efficacy of these medications. To address this gap, we will evaluate the effect of ethanol on the disposition of oseltamivir, an hCE1 substrate, and aspirin, an hCE2 substrate, in humans.
Normal healthy volunteers will report to the University of Tennessee Health Science Center Clinical Research Center (CRC) for a 10 hour stay on four separate days and receive each of the following treatments in random order:
- Oseltamivir (Tamiflu®) 150 mg. Subjects will drink orange juice (about 10 ounces although the amount may vary slightly based on weight) over 15 minutes. Fifteen minutes after drinking the orange juice, subjects will receive two (2) 75 mg capsules of oseltamivir with 5 ounces of water. Blood samples (1 teaspoonful) to determine the amount of oseltamivir in blood will be collected before the dose and 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10, and 24 hours hours after the dose. Subjects will be allowed to leave the CRC after the 10 hour blood sample is collected and return the following day for the 24 hour sample.
- Oseltamivir (Tamiflu®) 150 mg + Ethanol. In this phase, subjects will drink the same amount of orange juice over 15 minutes that will now have ethanol (alcohol) added. The amount of ethanol that will be added is calculated to achieve a blood alcohol concentration of 0.08 g/dl, which is considered to be legally intoxicated. Fifteen minutes after drinking the orange juice + ethanol, subjects will receive two (2) 75 mg capsules of oseltamivir with 5 ounces of water. Blood samples will be collected at the same times as above. An additional blood sample (1 teaspoonful) for determining the blood alcohol concentration will be collected 30 minutes after drinking the orange juice + ethanol.
- Aspirin 650 mg. Subjects will drink orange juice (about 10 ounces although the amount may vary slightly based on your weight) over 15 minutes. Fifteen minutes after drinking the orange juice, they will take two (2) 325 mg aspirin tablets with 5 oz of water. Blood samples to determine the amount of aspirin in the blood will be collected before the aspirin dose and at 10, 20, and 30 minutes after the dose and at 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 7.0, and 8.0 hours after the dose.
- Aspirin 650 mg + Ethanol. In this phase, subjects will drink the same amount of orange juice over 15 minutes that will now have ethanol (alcohol) added. The amount of ethanol that will be added is calculated to achieve a blood alcohol concentration of 0.08 g/dl, which is considered to be legally intoxicated. Fifteen minutes after drinking the orange juice + ethanol, subjects will take two (2) 325 mg aspirin tablets with 5 ounces of water. Blood samples (1 teaspoonful) to determine the amount of aspirin in the blood will be collected before the aspirin dose and at 10, 20, and 30 minutes after the dose and at 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 7.0, and 8.0 hours after the dose.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Oseltamivir & Placebo | Active comparator | Drug: Placebo, Drug: OseltamivirOseltamivir 150 mg orally will be administered 15 minutes after subjects consume orange juice |
| Oseltamivir & Ethanol | Experimental | Drug: Ethanol, Drug: OseltamivirOseltamivir 150 mg and ethanol targeted to blood alcohol concentration 0.08 g/dl |
| Aspirin & Placebo | Active comparator | Drug: Placebo, Drug: AspirinAspirin 650 mg orally will be administered 15 minutes after subjects consume orange juice |
| Aspirin & Ethanol | Experimental | Drug: Ethanol, Drug: AspirinAspirin 650 mg and ethanol targeted to blood alcohol concentration 0.08 g/dl |
Who may qualify
- Ages
- 21 to 45 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (2 listed)
- Healthy volunteers ages 21-45 with no chronic medical or psychiatric conditions
- social ethanol drinker
Key exclusion criteria (10 listed)
- allergy or hypersensitivity to oseltamivir or aspirin
- concomitant medication treatment (either prescription, over the counter, herbals, or supplements such as vitamins
- co-existing diseases affecting cardiovascular, hepatic, renal, pulmonary, hematologic, or gastrointestinal function
- platelet count < 100,000, hematocrit < 30
- chronic psychiatric disorder
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PlaceboAlso: Tropicana orange juiceOrange juice administered 15 minutes before subjects take oseltamivir or aspirin | Drug | Aspirin & Placebo, Oseltamivir & Placebo |
| EthanolAlso: Ethanol plus Tropicana orange juiceEthanol will be mixed with orange juice and subjects will drink the mixture 15 minutes before receiving oseltamivir or aspirin | Drug | Aspirin & Ethanol, Oseltamivir & Ethanol |
| OseltamivirAlso: TamifluOseltamivir 150 mg orally | Drug | Oseltamivir & Ethanol, Oseltamivir & Placebo |
| AspirinAspirin 650 mg orally will be given | Drug | Aspirin & Ethanol, Aspirin & Placebo |
Primary outcome
Area under the plasma concentration-time curve
Time frame: Oseltamivir 0-24 hrs; Aspirin 0-8 hours
For determining if ethanol inhibits hCE1 or hCE2, the primary pharmacokinetic parameter of interest will be the area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) for oseltamivir phosphate and acetylsalicylic acid, respectively. Other pharmacokinetic parameters that will be characterized are maximum plasma concentration (Cmax), time to reach the maximum plasma concentration (tmax), and the elimination rate constant λz. This same pharmacokinetic analysis will also be applied to the oseltamivir carboxylate and salicylic acid metabolites. The change in the metabolite formation clearance (∆Clf) for each agent will be calculated as the ratio of the metabolite to parent AUC0-∞ when given with ethanol (inh) and alone (con) as follows: ΔClf = [AUCm/AUCp]inh/[AUCm/AUCp]con
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Oct 2012.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Robert B Parker, PharmD principal investigator
University of Tennessee
Steven C Laizure, PharmD principal investigator
University of Tennessee
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Ethanol, Oseltamivir and Aspirin in people with Drug Interactions, run by University of Tennessee at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 16 Oct 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Area under the plasma concentration-time curve (time frame: Oseltamivir 0-24 hrs; Aspirin 0-8 hours). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Oct 2012.