Identification of New Tools for Predicting Natural Metabolic Performance of the Liver

NCT07014930 | Recruiting Phase 1 DMC

• 1 other identifier: 2023-01956
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

The objective of this clinical trial is to identify endogenous compounds (substances naturally present in the human body) that may serve as predictors of the activity of a key liver enzyme, CYP2C19. This enzyme plays a crucial role in the metabolism of several important drugs and exhibits significant interindividual variability in its activity, which can contribute to adverse drug reactions or reduced therapeutic efficacy. The study will involve 40 healthy volunteers, divided into two groups: 10 poor metabolizers and 30 non-poor metabolizers. Each participant will undergo three sessions. In the first session, 24-hour urine collection and plasma sampling will be conducted. Omeprazole will be administered orally, and the baseline blood OH-omeprazole/omeprazole ratio will be determined via capillary blood sampling. The second session, identical in procedure to the first, will take place after 7 days of fluvoxamine administration (inhibition phase). The third session will also mirror the first but will follow 10 days of rifampicin administration (induction phase). Endogenous compounds showing significant variation across sessions and between metabolizer groups will be evaluated as potential biomarkers for predicting CYP2C19 activity.

Conditions

Healthy Volunteers

Outcome Measures

Primary Outcomes (1)

• Fold-change in the intensities of features determined by mass spectrometry according to genotype (PMs versus NMs-RMs-UMs) and according to sessions.

  Metabolic features showing a fold-change ≥ 1.5 or ≤ 0.6737 will be qualified as CYP2C19 endogenous biomarkers. Chromatographic signals will be detected in healthy volunteers' urine, plasma and liver-derived extracellular vesicles by liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS) at each session for each volunteer.

  Samples collected at Session 1 (Day 1), Session 2 (Day 11 ± 4), and Session 3 (Day 27 ± 4); data analysis completed within 90 days after the final session of the last participant.

Secondary Outcomes (2)

• Correlation of significant ions measured in metabolomics with OH-OPZ/OPZ blood ratio.

  Within 90 days after the last study session of the last participant.

• Predictive performance metrics of a multivariate linear regression model for CYP2C19 phenotype.

  Within 90 days after the last study session of the last participant.

Study Arms (2)

CYP2C19 Poor Metabolizers (PMs)

EXPERIMENTAL

Carriers of two non-functional alleles of CYP2C19

Drug: Control session; Drug: Inhibition session; Drug: Induction session

CYP2C19 Normal, Rapid or Ultrarapid Metabolizers (NMs-RMs-UMs)

EXPERIMENTAL

Carriers of two normally functional alleles (NMs), one normally functional allele and one increased-functional allele (RMs) or two increased-functional alleles of CYP2C19 (UMs).

Drug: Control session; Drug: Inhibition session; Drug: Induction session

Interventions

Control session DRUG

Plasma and urine sampling as well as the determination of the blood OH-omeprazole/omeprazole ratio at baseline by capillary blood sampling.

CYP2C19 Normal, Rapid or Ultrarapid Metabolizers (NMs-RMs-UMs); CYP2C19 Poor Metabolizers (PMs)

Inhibition session DRUG

Plasma and urine sampling as well as the determination of the blood OH-omeprazole/omeprazole ratio at baseline by capillary blood sampling, with prior administration of 50 mg of fluvoxamine for 7 consecutive days (CYP2C19 inhibitor).

CYP2C19 Normal, Rapid or Ultrarapid Metabolizers (NMs-RMs-UMs); CYP2C19 Poor Metabolizers (PMs)

Induction session DRUG

Plasma and urine sampling as well as the determination of the blood OH-omeprazole/omeprazole ratio at baseline by capillary blood sampling, with prior administration of 600 mg of rifampicin for 10 consecutive days (CYP2C19 inducer).

CYP2C19 Normal, Rapid or Ultrarapid Metabolizers (NMs-RMs-UMs); CYP2C19 Poor Metabolizers (PMs)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Healthy men and women
• Age 18-65 years
• Body Mass Index (BMI) 18-27
• Understanding of French language and able to give a written inform consent
• CYP2C19 genotype: PMs, NMs, RMs or UMs
• At least one barrier method contraception during the whole study and 1 month after the end of the study (in addition of hormonal contraception if applicable)

You may not qualify if:

• CYP2C19 IMs
• Pregnant or breastfeeding woman
• Any pathologies, use of drugs or food that may affect CYP activity (based on the 'drug interactions and cytochromes P450 table published by the Service of Clinical Pharmacology and Toxicology, HUG50 and on the investigator's knowledge)
• Medical history of liver transplantation
• Regular smokers of ≥ 10 cigarettes/day
• Alcohol intake 2 days prior to session 1 and during fluvoxamine and rifampicin intake
• Alteration of hepatic tests (ASAT, ALAT, GGT, bilirubin more than 3x normal)
• Renal failure (serum urea, serum creatinine and eGFR outside the norms)
• Medical history of chronic alcoholism or abuse of psychoactive drugs
• Sensitivity to any of the drugs used
• Psychiatric disorders
• Beck Score ≥10 (question related to suicide \>0)
• Contact lens wearers

Sponsors & Collaborators

• Caroline Samer: lead
• Fonds national Suisse: collaborator

Study Sites (1)

The Geneva University Hospitals (HUG)

Geneva, 1211, Switzerland

RECRUITING

Central Study Contacts

Yahia Bennani, Master's degree

CONTACT

+41 78 733 14 23; yahia.bennani@hug.ch

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: May 19, 2025
• First Posted: June 11, 2025
• Study Start: December 5, 2024
• Primary Completion: November 1, 2025
• Study Completion: January 1, 2026
• Last Updated: June 11, 2025

Record last verified: 2025-06

Locations

CH (1)