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Genetic Determinants of ACEI Prodrug Activation

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03051282
Recruitment Status : Suspended (Enrollment and interactions/interventions are paused due to COVID-19 and are expected to resume in the future. This is not a suspension of IRB approval.)
First Posted : February 13, 2017
Last Update Posted : June 19, 2020
Sponsor:
Information provided by (Responsible Party):
Haojie Zhu, University of Michigan

Brief Summary:
Angiotensin-converting enzyme inhibitors (ACEIs) are among the most frequently prescribed medications worldwide for the treatment of essential hypertension, left ventricular systolic dysfunction, acute myocardial infarction, and prevention of the progression of diabetic nephropathy. However, the outcome of ACEI treatment varies significantly between individuals and selected populations. Suboptimal response, therapeutic failure, and significant side effects are commonly documented in patients receiving ACEI therapy. Approximately 80% of the ACEIs available for use in the US are synthesized as esterified prodrugs in order to improve otherwise poor oral bioavailability of the active molecule. The activation of ACEI prodrugs primarily occurs in the liver via metabolic de-esterification of the parent drug. The critical activation step is essential in delivering a successful therapeutic outcome since the active metabolites are approximately 10-1000 times more potent relative to their respective parent compounds. Carboxylesterase 1 (CES1), the most abundant hydrolase in the liver, is responsible for the activation of ACEI prodrugs in humans. Marked interindividual variability in CES1 expression and activity has been documented, which results in varied therapeutic efficacy and tolerability of many drugs serving as substrates of CES1. Genetic variation of CES1 is considered to be a major factor contributing to variability in CES1 function. The study team proposes to conduct a multiple-dose healthy volunteer study to evaluate the impact of CES1 genetic variation on the activation, pharmacokinetics, and pharmacodynamics of enalapril, a model ACEI prodrug activated by CES1. The completion of this study will represent a major step towards the establishment of an evidence base from which a more individualized use of ACEI prodrugs can emerge.

Condition or disease Intervention/treatment Phase
Healthy Volunteers Drug: Enalapril Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Screening
Official Title: Genetic Determinants of ACEI Prodrug Activation
Actual Study Start Date : April 1, 2017
Estimated Primary Completion Date : January 2021
Estimated Study Completion Date : January 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: non-carrier control group
Subjects who do not carry the CES1 variant G143E (rs71647871) will receive 10 mg Enalapril orally once daily for 7 consecutive days.
Drug: Enalapril
Study participants in both arms will be treated with 10 mg enalapril orally once daily for seven consecutive days
Other Name: Vasotec®

Active Comparator: G143E carriers group
Subjects who carry the CES1 variant G143E (rs71647871) will receive 10 mg Enalapril orally once daily for 7 consecutive days.
Drug: Enalapril
Study participants in both arms will be treated with 10 mg enalapril orally once daily for seven consecutive days
Other Name: Vasotec®




Primary Outcome Measures :
  1. The measurements of the mean area under the curve (AUC) of enalaprilat plasma concentrations [ Time Frame: 72 hours ]
    To compare the mean AUC of enalaprilat plasma concentrations between the non-carrier control and the G143E carriers groups


Secondary Outcome Measures :
  1. The measurements of the maximum enalaprilat plasma concentrations [ Time Frame: 72 hours ]
    To compare the maximum enalaprilat plasma concentrations between the non-carrier control and the G143E carriers groupsG143E carriers groups

  2. The measurements of angiotensin converting enzyme (ACE) activity in plasma [ Time Frame: 72 hours ]
    To compare the plasma ACE activity between the non-carrier control and the G143E carriers groupsG143E carriers groups following enalapril treatment

  3. The measurements of blood pressures (BPs) following enalapril treatment [ Time Frame: 72 hours ]
    To compare the changes of BPs between the non-carrier control and the G143E carriers groupsG143E carriers groups following enalapril treatment



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Subjects must be male and female (50:50) between the ages of 18-55 years
  • Females must have a negative urine pregnancy test prior to the study
  • All subjects must have no clinically significant diseases or clinically significant abnormal laboratory values as assessed during the screening medical history, nursing assessment, and laboratory evaluations
  • Informed consent must be signed by the eligible subject prior to the initiation of any study procedures

Exclusion Criteria:

  • The presence of a known medical condition that would preclude the use of enalapril
  • The presence of any surgical or medical condition (active or chronic) that may interfere with drug absorption, distribution, metabolism, or excretion.
  • A positive urine pregnancy test in the MCRU prior to the study
  • No subjects weighing under 50 kg will be selected
  • The lack of use of acceptable methods of birth control unless abstinent
  • Subjects who regularly take medications, vitamins, herbal supplements
  • The use of any illicit drugs or habitual consumption of large quantities of ethanol (>3 drinks/day)
  • The consumption of grapefruit or grapefruit juice a week prior to, and during the study
  • Asians will not be included in the study as the CES1 SNP G143E is absent in this population
  • Subjects hypersensitive to enalapril
  • Subject with a history of angioedema
  • Smokers

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03051282


Locations
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United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
Sponsors and Collaborators
University of Michigan
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Responsible Party: Haojie Zhu, Associate Professor, University of Michigan
ClinicalTrials.gov Identifier: NCT03051282    
Other Study ID Numbers: HUM00114879
First Posted: February 13, 2017    Key Record Dates
Last Update Posted: June 19, 2020
Last Verified: June 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Enalapril
Angiotensin-Converting Enzyme Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antihypertensive Agents