Genetic Factors in Enalapril Activation for Healthy Subjects

Overseen By Haojie Zhu, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Phase 4

Sponsor: University of Michigan

Must not be taking: Illicit drugs, Ethanol

Disqualifiers: Underweight, Asians, Angioedema, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 72

Duration: 1 week

30 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

Yes, you will need to stop taking your current medications, vitamins, and herbal supplements to participate in this trial.

What data supports the effectiveness of the drug Enalapril?

Research shows that Enalapril is converted in the body to an active form called enalaprilat, which helps lower blood pressure in patients with hypertension (high blood pressure). The effectiveness of Enalapril can vary based on genetic factors, but it is generally used to manage high blood pressure by relaxing blood vessels. ^{1 2 3 4 5}

Is enalapril generally safe for humans?

Enalapril has been studied in both patients with high blood pressure and healthy volunteers, and no significant safety concerns have been reported. Variations in the CES1 gene can affect how the body processes enalapril, but these differences are not considered to have a clinically relevant impact on safety. ^{1 4 5 6 7}

How does the drug enalapril differ from other treatments?

Enalapril is unique because its effectiveness can be influenced by genetic variations in the CES1 gene, which affects how the body converts it into its active form, enalaprilat. This means that genetic testing could help personalize enalapril treatment for better results, unlike other treatments that don't consider genetic factors. ^{1 4 5 6 8}

Eligibility Criteria

This trial is for healthy men and women aged 18-55, with a balanced gender ratio. Participants must not have significant diseases or abnormal lab results, be non-smokers, not pregnant, and use birth control if applicable. Asians are excluded due to genetic reasons related to the study's focus.

Inclusion Criteria

I am between 18 and 55 years old.

Informed consent must be signed by the eligible subject prior to the initiation of any study procedures

Exclusion Criteria

I do not have any conditions that prevent me from taking enalapril.

I regularly take medications, vitamins, or herbal supplements.

The use of any illicit drugs or habitual consumption of large quantities of ethanol (>3 drinks/day)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 10 mg Enalapril orally once daily for 7 consecutive days

1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 week

Follow-up assessments over 72 hours

Treatment Details

Interventions

• Enalapril

Trial Overview The trial studies how genetic differences affect the body's ability to activate Enalapril, a common drug for high blood pressure and heart issues. It looks at how well different people process the drug because of their unique genes.

Participant Groups

Group I: non-carrier control group Active Control 1 Intervention

Subjects who do not carry the CES1 variant G143E (rs71647871) will receive 10 mg Enalapril orally once daily for 7 consecutive days.

Group II: G143E carriers group Active Control 1 Intervention

Subjects who carry the CES1 variant G143E (rs71647871) will receive 10 mg Enalapril orally once daily for 7 consecutive days.

Who Is Running the Clinical Trial?

University of Michigan

Lead Sponsor

Trials

1,891

Recruited

6,458,000+

Findings from Research

In a study of 43 healthy Danish volunteers, variations in the carboxylesterase 1 gene (CES1) did not significantly affect the pharmacokinetics of enalapril, indicating that genetic differences in CES1 do not have a clinically relevant impact on how the drug is metabolized.

While the terminal half-life of the active metabolite enalaprilat was longer in one genetic group, this difference was not considered clinically significant, suggesting that enalapril can be used effectively across different CES1 genotypes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Pharmacokinetics of Enalapril in Relation to CES1 Genotype in Healthy Danish Volunteers. Stage, C., Jürgens, G., Guski, LS., et al.[2018]

Hypertension affects many people, but only about one-third of those aware of their condition manage to control their blood pressure effectively, partly due to unpredictable responses to treatment.

While research into hypertension pharmacogenetics has identified some genetic predictors of drug response, inconsistencies in study designs and small sample sizes have limited clinical application, highlighting the need for larger, more diverse studies in the future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacogenetics of antihypertensive treatment: detailing disciplinary dissonance. Arnett, DK., Claas, SA.[2021]

A review of 28 studies on genetic predictors of blood pressure response to anti-hypertensive medications found that most research focused on single nucleotide polymorphisms (SNPs) related to the renin-angiotensin system, but no definitive conclusions were reached.

Despite the interest in using genetic information to predict individual responses to blood pressure medications, the studies primarily used small candidate-gene designs and did not demonstrate clear prognostic value compared to standard clinical practices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacogenetics of hypertension treatment: a structured review. Koopmans, RP., Insel, PA., Michel, MC.[2019]

In a study of 286 Caucasian patients with hypertension, genetic variations in the CES1 gene significantly influenced the levels of the active metabolite enalaprilat after enalapril administration, indicating that genetics can affect drug metabolism.

Patients with certain CES1 gene variants had up to 75% lower concentrations of enalaprilat, suggesting that pharmacogenetic testing could help tailor enalapril prescriptions for better individual treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Influence of the CES1 Genotype on the Pharmacokinetics of Enalapril in Patients with Arterial Hypertension. Ikonnikova, A., Rodina, T., Dmitriev, A., et al.[2023]

In a study of 286 Caucasian patients with hypertension, specific genetic variants in the CES1 gene were found to significantly reduce the metabolism of enalapril to its active form, enalaprilat, leading to lower plasma concentrations.

Carriers of the CES1A2 haplotype exhibited decreased CES1 activity, which affects the pharmacokinetics of enalapril, highlighting the importance of considering these genetic factors in personalized treatment plans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Influence of Structural Variants of the CES1 Gene on the Pharmacokinetics of Enalapril, Presumably Due to Linkage Disequilibrium with the Intronic rs2244613. Ikonnikova, A., Kazakov, R., Rodina, T., et al.[2023]

The CES1 c.428G>A genetic variation in healthy volunteers resulted in a 20% lower plasma concentration of the active form of enalaprilat compared to those without the variation, indicating a potential impact on drug efficacy.

This genetic variation also led to a 35% reduction in the urinary excretion of enalaprilat, suggesting that the CES1 genotype may affect the metabolism of enalapril but does not influence the pharmacokinetics of quinapril.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of carboxylesterase 1 c.428G > A single nucleotide variation on the pharmacokinetics of quinapril and enalapril. Tarkiainen, EK., Tornio, A., Holmberg, MT., et al.[2018]

The CES1 G143E genetic variant significantly reduces the activation of enalapril, leading to a 30.9% lower peak concentration of its active form, enalaprilat, in carriers compared to non-carriers.

Carriers of the G143E variant experienced no significant reduction in blood pressure after enalapril treatment, while non-carriers showed an average reduction of 12.4%, indicating that this genetic variant impairs the drug's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of CES1 genetic variation on enalapril steady-state pharmacokinetics and pharmacodynamics in healthy subjects. Her, LH., Wang, X., Shi, J., et al.[2022]

The IDEAL trial involved 124 untreated hypertensive patients aged 25 to 70, aiming to identify markers that influence blood pressure responses to ACE inhibitors and diuretics.

Results showed an average blood pressure reduction of about 2% at each visit before randomization, highlighting the importance of understanding individual responses to these medications for personalized treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The IDEAL study : towards personalized drug treatment of hypertension. Bejan-Angoulvant, T., Baguet, JP., Erpeldinger, S., et al.[2015]

References

1. England pubmed.ncbi.nlm.nih.gov

The Pharmacokinetics of Enalapril in Relation to CES1 Genotype in Healthy Danish Volunteers. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Pharmacogenetics of antihypertensive treatment: detailing disciplinary dissonance. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Pharmacogenetics of hypertension treatment: a structured review. [2019]

4. Switzerland pubmed.ncbi.nlm.nih.gov

The Influence of the CES1 Genotype on the Pharmacokinetics of Enalapril in Patients with Arterial Hypertension. [2023]

5. Switzerland pubmed.ncbi.nlm.nih.gov

The Influence of Structural Variants of the CES1 Gene on the Pharmacokinetics of Enalapril, Presumably Due to Linkage Disequilibrium with the Intronic rs2244613. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Effect of carboxylesterase 1 c.428G > A single nucleotide variation on the pharmacokinetics of quinapril and enalapril. [2018]

7. England pubmed.ncbi.nlm.nih.gov

Effect of CES1 genetic variation on enalapril steady-state pharmacokinetics and pharmacodynamics in healthy subjects. [2022]

8. France pubmed.ncbi.nlm.nih.gov

The IDEAL study : towards personalized drug treatment of hypertension. [2015]