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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how genetic differences affect the body's response to enalapril, a common medication for high blood pressure and heart issues. The focus is on understanding how a specific gene variation, called CES1, influences the drug's activation in the liver, impacting its effectiveness and side effects. Researchers will divide participants into two groups based on the presence of this genetic variation. This study is best suited for healthy individuals without significant medical conditions and who do not regularly use medications or supplements. As a Phase 4 trial, enalapril is already FDA-approved and proven effective, and this research aims to understand how it benefits more patients.

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 is the safety track record for this treatment?

Research has shown that enalapril, a medication for high blood pressure, has been tested in both patients with this condition and healthy individuals. These studies have not identified any major safety concerns. Most people tolerate enalapril well, but its effectiveness can vary due to a liver enzyme called CES1, which activates the drug in the body. A genetic variation known as G143E can alter this enzyme's function, affecting the drug's effectiveness and safety. However, current evidence indicates that enalapril is safe for most people, with no significant issues reported. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Enalapril is unique because it targets the CES1 genetic variant G143E, potentially offering more personalized treatment for patients with this genetic makeup. Most treatments for hypertension, like other ACE inhibitors, don’t account for genetic differences in drug activation. This focus on genetic factors could lead to more effective blood pressure management and fewer side effects for individuals with the G143E variant, which is why researchers are excited about its potential.

What is the effectiveness track record for Enalapril in treating hypertension?

Research has shown that enalapril, a medicine for high blood pressure, does not work the same for everyone. Genetic differences in a liver enzyme called CES1, which activates enalapril, primarily cause this variation. This trial will compare two groups: participants with the specific genetic variant G143E and those without it. Studies have found that the G143E variant can reduce enalapril's effectiveness in lowering blood pressure. Individuals with this variant may not benefit as much from the treatment as those without it. Understanding these genetic differences can lead to more effective treatments. ^{2 6 7 8 9}

Are You a Good Fit for This Trial?

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

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

Exclusion Criteria

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

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

I regularly take medications, vitamins, or herbal supplements.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

Citations

1. bpspubs.onlinelibrary.wiley.com bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.14888

Effect of CES1 genetic variation on enalapril steady‐state ... The CES1 loss-of-function G143E variant significantly impaired enalapril activation and its systolic blood pressure-lowering effect in healthy volunteers.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33963573/

Effect of CES1 genetic variation on enalapril steady-state ... The CES1 loss-of-function G143E variant significantly impaired enalapril activation and its systolic blood pressure-lowering effect in healthy volunteers.

3. bpspubs.onlinelibrary.wiley.com bpspubs.onlinelibrary.wiley.com/doi/am-pdf/10.1111/bcp.14888

Effect of CES1 genetic variation on enalapril steady‐state ... This multi-dose enalapril healthy volunteer PK study demonstrated that the CES1 G143E variant significantly reduced enalapril activation and its blood pressure ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9028383/

The Influence of the CES1 Genotype on ... Previous studies show that variant rs71647871 in the CES1 gene affects the pharmacokinetics of enalapril on liver samples as well as healthy volunteers.

5. mdpi.com mdpi.com/2073-4425/13/12/2225

The Influence of Structural Variants of the CES1 Gene on ... Summarizing our results, we can conclude that CES1 activity is reduced against enalapril in carriers of the rs2244613 allele C, in patients with ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9778508/

The Influence of Structural Variants of the CES1 Gene on ... Variants in the CES1 gene encoding carboxylesterase 1 may affect the metabolism of enalapril to the active metabolite enalaprilat.

7. mdpi.com mdpi.com/2075-4426/12/4/580

The Influence of the CES1 Genotype on ... Previous studies show that variant rs71647871 in the CES1 gene affects the pharmacokinetics of enalapril on liver samples as well as healthy volunteers.

8. researchgate.net researchgate.net/figure/CES1-mediated-enalapril-activation_fig1_351438703

CES1‐mediated enalapril activation The G143E variant can affect the functionality of CES1, thus, affecting the efficacy and safety of drugs that rely on CES1 for activation/inactivation, ...

9. withpower.com withpower.com/trial/phase-4-3-2017-003b1

Genetic Factors in Enalapril Activation for Healthy Subjects Enalapril has been studied in both patients with high blood pressure and healthy volunteers, and no significant safety concerns have been reported. Variations ...