<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01708369</url>
  </required_header>
  <id_info>
    <org_study_id>R15GM096074</org_study_id>
    <nct_id>NCT01708369</nct_id>
  </id_info>
  <brief_title>Alcohol Inhibits Drug Metabolism by Carboxylesterases</brief_title>
  <official_title>Inhibition of Carboxylesterase Metabolism by Ethanol</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Tennessee</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Tennessee</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine if alcohol is able the affect the body's ability to&#xD;
      eliminate two commonly used medication, oseltamivir and aspirin. We hypothesize that drinking&#xD;
      alcohol may reduce the body's ability to break down these two medications along with many&#xD;
      others.This could affect the amount of drug in the blood which could impact how well these&#xD;
      drugs work and whether patients have side effects.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Carboxylesterases are enzymes that metabolize a growing number of commonly used medications.&#xD;
      In humans, two carboxylesterases, carboxylesterase-1 (hCE1) and carboxylesterase-2 (hCE2),&#xD;
      found primarily in the liver and intestine respectively, play an important role in the&#xD;
      biotransformation of numerous classes of commonly used drugs containing ester groups&#xD;
      including ACE inhibitors, anticancer agents, opiate analgesics, HMG-CoA reductase inhibitors&#xD;
      (statins), CNS stimulants, antiviral medications, and antiplatelet agents.&#xD;
&#xD;
      Factors affecting the activity of carboxylesterases would be expected to markedly alter the&#xD;
      pharmacokinetics and clinical effects of substrate drugs. One key factor that could affect&#xD;
      catalytic activity is drug interactions that inhibit carboxylesterase function. The&#xD;
      importance of inhibition of drug metabolism in medication safety and efficacy is well&#xD;
      established for drugs that undergo metabolism by cytochrome P450 enzymes. In distinct&#xD;
      contrast, little is known about the potential for carboxylesterases to serve as a target for&#xD;
      metabolic inhibition mediated by drug interactions.&#xD;
&#xD;
      It is well established that ethanol is an inhibitor of cocaine metabolism, a drug that is&#xD;
      eliminated by carboxylesterase hydrolysis. We propose that the ethanol-mediated inhibition of&#xD;
      carboxylesterases activity demonstrated with cocaine metabolism will occur with other&#xD;
      substrate drugs. This has widespread implications because of the large number of drugs that&#xD;
      are carboxylesterase substrates. In the United States, over 100 million people consume&#xD;
      ethanol making co-ingestion with carboxylesterase substrate drugs a common occurrence. We&#xD;
      believe that this is a prevalent drug interaction that is largely overlooked and has not been&#xD;
      systematically evaluated, but may importantly affect the disposition, safety, and efficacy of&#xD;
      these medications. To address this gap, we will evaluate the effect of ethanol on the&#xD;
      disposition of oseltamivir, an hCE1 substrate, and aspirin, an hCE2 substrate, in humans.&#xD;
&#xD;
      Normal healthy volunteers will report to the University of Tennessee Health Science Center&#xD;
      Clinical Research Center (CRC) for a 10 hour stay on four separate days and receive each of&#xD;
      the following treatments in random order:&#xD;
&#xD;
        1. Oseltamivir (Tamiflu®) 150 mg. Subjects will drink orange juice (about 10 ounces&#xD;
           although the amount may vary slightly based on weight) over 15 minutes. Fifteen minutes&#xD;
           after drinking the orange juice, subjects will receive two (2) 75 mg capsules of&#xD;
           oseltamivir with 5 ounces of water. Blood samples (1 teaspoonful) to determine the&#xD;
           amount of oseltamivir in blood will be collected before the dose and 0.5, 1.0, 1.5, 2.0,&#xD;
           3.0, 4.0, 6.0, 8.0, 10, and 24 hours hours after the dose. Subjects will be allowed to&#xD;
           leave the CRC after the 10 hour blood sample is collected and return the following day&#xD;
           for the 24 hour sample.&#xD;
&#xD;
        2. Oseltamivir (Tamiflu®) 150 mg + Ethanol. In this phase, subjects will drink the same&#xD;
           amount of orange juice over 15 minutes that will now have ethanol (alcohol) added. The&#xD;
           amount of ethanol that will be added is calculated to achieve a blood alcohol&#xD;
           concentration of 0.08 g/dl, which is considered to be legally intoxicated. Fifteen&#xD;
           minutes after drinking the orange juice + ethanol, subjects will receive two (2) 75 mg&#xD;
           capsules of oseltamivir with 5 ounces of water. Blood samples will be collected at the&#xD;
           same times as above. An additional blood sample (1 teaspoonful) for determining the&#xD;
           blood alcohol concentration will be collected 30 minutes after drinking the orange juice&#xD;
           + ethanol.&#xD;
&#xD;
        3. Aspirin 650 mg. Subjects will drink orange juice (about 10 ounces although the amount&#xD;
           may vary slightly based on your weight) over 15 minutes. Fifteen minutes after drinking&#xD;
           the orange juice, they will take two (2) 325 mg aspirin tablets with 5 oz of water.&#xD;
           Blood samples to determine the amount of aspirin in the blood will be collected before&#xD;
           the aspirin dose and at 10, 20, and 30 minutes after the dose and at 1.0, 1.5, 2.0, 2.5,&#xD;
           3.0, 4.0, 5.0, 6.0, 7.0, and 8.0 hours after the dose.&#xD;
&#xD;
        4. Aspirin 650 mg + Ethanol. In this phase, subjects will drink the same amount of orange&#xD;
           juice over 15 minutes that will now have ethanol (alcohol) added. The amount of ethanol&#xD;
           that will be added is calculated to achieve a blood alcohol concentration of 0.08 g/dl,&#xD;
           which is considered to be legally intoxicated. Fifteen minutes after drinking the orange&#xD;
           juice + ethanol, subjects will take two (2) 325 mg aspirin tablets with 5 ounces of&#xD;
           water. Blood samples (1 teaspoonful) to determine the amount of aspirin in the blood&#xD;
           will be collected before the aspirin dose and at 10, 20, and 30 minutes after the dose&#xD;
           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.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>February 2012</start_date>
  <completion_date type="Actual">May 2012</completion_date>
  <primary_completion_date type="Actual">May 2012</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Area under the plasma concentration-time curve</measure>
    <time_frame>Oseltamivir 0-24 hrs; Aspirin 0-8 hours</time_frame>
    <description>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</description>
  </primary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">19</enrollment>
  <condition>Drug Interactions</condition>
  <arm_group>
    <arm_group_label>Oseltamivir &amp; Placebo</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Oseltamivir 150 mg orally will be administered 15 minutes after subjects consume orange juice</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Oseltamivir &amp; Ethanol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Oseltamivir 150 mg and ethanol targeted to blood alcohol concentration 0.08 g/dl</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Aspirin &amp; Placebo</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Aspirin 650 mg orally will be administered 15 minutes after subjects consume orange juice</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Aspirin &amp; Ethanol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Aspirin 650 mg and ethanol targeted to blood alcohol concentration 0.08 g/dl</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Orange juice administered 15 minutes before subjects take oseltamivir or aspirin</description>
    <arm_group_label>Aspirin &amp; Placebo</arm_group_label>
    <arm_group_label>Oseltamivir &amp; Placebo</arm_group_label>
    <other_name>Tropicana orange juice</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ethanol</intervention_name>
    <description>Ethanol will be mixed with orange juice and subjects will drink the mixture 15 minutes before receiving oseltamivir or aspirin</description>
    <arm_group_label>Aspirin &amp; Ethanol</arm_group_label>
    <arm_group_label>Oseltamivir &amp; Ethanol</arm_group_label>
    <other_name>Ethanol plus Tropicana orange juice</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Oseltamivir</intervention_name>
    <description>Oseltamivir 150 mg orally</description>
    <arm_group_label>Oseltamivir &amp; Ethanol</arm_group_label>
    <arm_group_label>Oseltamivir &amp; Placebo</arm_group_label>
    <other_name>Tamiflu</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Aspirin</intervention_name>
    <description>Aspirin 650 mg orally will be given</description>
    <arm_group_label>Aspirin &amp; Ethanol</arm_group_label>
    <arm_group_label>Aspirin &amp; Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy volunteers ages 21-45 with no chronic medical or psychiatric conditions&#xD;
&#xD;
          -  social ethanol drinker&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  allergy or hypersensitivity to oseltamivir or aspirin&#xD;
&#xD;
          -  concomitant medication treatment (either prescription, over the counter, herbals, or&#xD;
             supplements such as vitamins&#xD;
&#xD;
          -  co-existing diseases affecting cardiovascular, hepatic, renal, pulmonary, hematologic,&#xD;
             or gastrointestinal function&#xD;
&#xD;
          -  platelet count &lt; 100,000, hematocrit &lt; 30&#xD;
&#xD;
          -  chronic psychiatric disorder&#xD;
&#xD;
          -  score &gt;2 on the Michigan Alcohol Screening Test (MAST)&#xD;
&#xD;
          -  naive to alcohol ingestion, have a family history of alcohol dependence, or history of&#xD;
             adverse responses to alcohol&#xD;
&#xD;
          -  women with known pregnancy, lactation, or not using and effective method of birth&#xD;
             control (subjects taking oral contraceptives will be excluded)&#xD;
&#xD;
          -  ingestion of alcohol or caffeine during the study&#xD;
&#xD;
          -  participation in another drug study or blood donation within the preceding weeks.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Robert B Parker, PharmD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Tennessee</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Steven C Laizure, PharmD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Tennessee</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Tennessee Health Science Center</name>
      <address>
        <city>Memphis</city>
        <state>Tennessee</state>
        <zip>38163</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2012</verification_date>
  <study_first_submitted>October 13, 2012</study_first_submitted>
  <study_first_submitted_qc>October 15, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 16, 2012</study_first_posted>
  <last_update_submitted>October 15, 2012</last_update_submitted>
  <last_update_submitted_qc>October 15, 2012</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 16, 2012</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Tennessee</investigator_affiliation>
    <investigator_full_name>Robbie Parker</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>human carboxylesterase-1</keyword>
  <keyword>human carboxylesterase-2</keyword>
  <keyword>alcohol</keyword>
  <keyword>pharmacokinetics</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aspirin</mesh_term>
    <mesh_term>Ethanol</mesh_term>
    <mesh_term>Oseltamivir</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01708369
org study id: R15GM096074
nct id: NCT01708369
lead sponsor: 
has dmc: No
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.
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:

        1. 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.

        2. 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.

        3. 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.

        4. 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.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Area under the plasma concentration-time curve
time frame: Oseltamivir 0-24 hrs; Aspirin 0-8 hours
description: 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
arm group label: Oseltamivir & Placebo
arm group type: Active Comparator
description: Oseltamivir 150 mg orally will be administered 15 minutes after subjects consume orange juice
arm group label: Oseltamivir & Ethanol
arm group type: Experimental
description: Oseltamivir 150 mg and ethanol targeted to blood alcohol concentration 0.08 g/dl
arm group label: Aspirin & Placebo
arm group type: Active Comparator
description: Aspirin 650 mg orally will be administered 15 minutes after subjects consume orange juice
arm group label: Aspirin & Ethanol
arm group type: Experimental
description: Aspirin 650 mg and ethanol targeted to blood alcohol concentration 0.08 g/dl
intervention type: Drug
intervention name: Placebo
description: Orange juice administered 15 minutes before subjects take oseltamivir or aspirin
arm group label: Aspirin & Placebo
arm group label: Oseltamivir & Placebo
other name: Tropicana orange juice
intervention type: Drug
intervention name: Ethanol
description: Ethanol will be mixed with orange juice and subjects will drink the mixture 15 minutes before receiving oseltamivir or aspirin
arm group label: Aspirin & Ethanol
arm group label: Oseltamivir & Ethanol
other name: Ethanol plus Tropicana orange juice
intervention type: Drug
intervention name: Oseltamivir
description: Oseltamivir 150 mg orally
arm group label: Oseltamivir & Ethanol
arm group label: Oseltamivir & Placebo
other name: Tamiflu
intervention type: Drug
intervention name: Aspirin
description: Aspirin 650 mg orally will be given
arm group label: Aspirin & Ethanol
arm group label: Aspirin & Placebo
criteria: 
gender: All
minimum age: 21 Years
maximum age: 45 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Robert B Parker, PharmD
role: Principal Investigator
affiliation: University of Tennessee
last name: Steven C Laizure, PharmD
role: Principal Investigator
affiliation: University of Tennessee
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Tennessee
investigator full name: Robbie Parker
investigator title: Professor
mesh term: Aspirin
mesh term: Ethanol
mesh term: Oseltamivir