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Genetic Determinants of ACEI Prodrug Activation

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

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.

Official Title

Genetic Determinants of ACEI Prodrug Activation

Quick Facts

Study Start:2017-04-01

Study Completion:2026-01-01

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:RECRUITING

Study ID

NCT03051282

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:18 Years to 55 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:Yes

Standard Ages:ADULT

Inclusion Criteria	Exclusion 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	* 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

Inclusion Criteria

Exclusion 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

* 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

Contacts and Locations

Study Contact

Haojie Zhu, PhD

CONTACT

7347638449

hjzhu@med.umich.edu

Study Locations (Sites)

University of Michigan

Ann Arbor, Michigan, 48109

United States

Collaborators and Investigators

Sponsor: University of Michigan

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2017-04-01

Study Completion Date2026-01-01

Study Record Updates

Study Start Date2017-04-01

Study Completion Date2026-01-01

Terms related to this study

Additional Relevant MeSH Terms

Healthy Volunteers