Risk of CYP2C19 Phenoconversion in Healthy Volunteers With Rapid, Normal, and Intermediate Predicted Metabolizers' Status

NCT05264142 | Unknown Phase 1

• 1 other identifier: 2022-XXXX
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 1

Brief Summary

CYP2C19 is responsible for the metabolism of approximately 10% of drugs currently on the market, including several proton pump inhibitors, clopidogrel, benzodiazepines and some tricyclic antidepressants, including amitriptyline. It is a cytochrome whose activity is characterized by a great variability in the general population. This variability can be explained, in part, by genetic and environmental factors The classification of phenotypes associated with CYP2C19 has evolved over time. Today, five distinct phenotypes are used to characterize this variability: the slow metabolizer (SM) phenotype, the intermediate metabolizer (IM) phenotype, the normal metabolizer (NM) phenotype, the fast metabolizer (RM) phenotype and finally the ultra-fast metabolizer (UM) phenotype. (UM) phenotype. Although directly measurable with test substances, CYP2C19 phenotypes are often assigned on the basis of genotype. They may be impacted by intrinsic (e.g., comorbidities) or extrinsic (e.g., co-medications) factors. Phenoconversion or phenotypic change is the phenomenon by which an individual switches from one phenotype to another due to an environmental influence such as a drug interaction. However, genotype is likely to influence the degree of response to a drug interaction. Vulnerability to phenoconversion therefore differs according to the genotype of the individual. The purpose of our study is to determine whether individuals genetically MR, NM and IM have the same vulnerability to phenoconversion. Thus, the magnitude of the response to CYP2C19 inhibition will be studied in these 3 groups of individuals (NM:\*1/\*1, RM:\*1/\*17 and IM:\*1/\*2-\*2/\*17). Inhibition will be studied in two steps, using a strong (fluvoxamine) and a weak (voriconazole) inhibitor of CYP2C19.

Conditions

Healthy

Keywords

Phenoconversion; Pharmakinetics; Genotype; Cytochrome 2C19

Outcome Measures

Primary Outcomes (1)

• Phenoconversion rate

  The proportion of volunteers in each group who acquire a phenotype switch such as from NM to PM after pre-treatment by voriconazole and fluvoxamine (weak and strong inhibitors, respectively)

  2 months

Secondary Outcomes (4)

• AUC assessment

  1 year

• CL assessment

  1 year

• Cmax assessment

  1 year

• Tmax assessment

  1 year

Study Arms (3)

CYP2C19 Rapid Metabolizers (RM)

EXPERIMENTAL

CYP2C19 rapid metabolizers (RM) are characterized by one normal function allele and one increased function allele

Drug: Voriconazole 200mg; Drug: FluvoxaMINE 50 Mg Oral Tablet; Drug: Omeprazole 10 MG Oral Tablet

CYP2C19 Normal metabolizers (NM)

EXPERIMENTAL

CYP2C19 normal metabolizers (NMs) harboring two normal function alleles defined by the lack of any characterized polymorphisms.

Drug: Voriconazole 200mg; Drug: FluvoxaMINE 50 Mg Oral Tablet; Drug: Omeprazole 10 MG Oral Tablet

CYP2C19 Intermediate metabolizers (IM)

EXPERIMENTAL

CYP2C19 intermediate metabolizers (IMs) are characterized by the presence of one normal function allele and one no function allele or one no function allele and one increased function allele.

Drug: Voriconazole 200mg; Drug: FluvoxaMINE 50 Mg Oral Tablet; Drug: Omeprazole 10 MG Oral Tablet

Interventions

Voriconazole 200mg DRUG

Voriconazole is a weak CYP2C19 inhibitor. It is used in study session 2 to study the impact of a weak inhibitor on the phenotype switch among the different genotypes included in the study.

Also known as: J02AC03

CYP2C19 Intermediate metabolizers (IM); CYP2C19 Normal metabolizers (NM); CYP2C19 Rapid Metabolizers (RM)

FluvoxaMINE 50 Mg Oral Tablet DRUG

Fluvoxamine is a strong CYP2C19 inhibitor. It is used in study session 3 to study the impact of a strong inhibitor on the phenotype switch among the different genotypes included in the study.

Also known as: N06AB08

CYP2C19 Intermediate metabolizers (IM); CYP2C19 Normal metabolizers (NM); CYP2C19 Rapid Metabolizers (RM)

Omeprazole 10 MG Oral Tablet DRUG

Omeprazole is a CYP2C19 probe substrate. It is used in the study as a tool for CYP2C19 phenotyping at each of the sessions.

Also known as: A02BC01

CYP2C19 Intermediate metabolizers (IM); CYP2C19 Normal metabolizers (NM); CYP2C19 Rapid Metabolizers (RM)

Eligibility Criteria

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

You may qualify if:

• Healthy men and women ≥ 18 years old
• Understanding of French language and able to give a written consent
• Reliable contraception during the whole study, including a barrier method
• CYP2C19 genotype associated to the RM (\*1/\*17) , NM(\*1/\*1) AND IM(\*1/\*2-\*2/\*17) activity groups

You may not qualify if:

• 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 Pharmacoloy and Toxicology, HUG and on the investigator's knowledge)
• History of liver transplantation
• Alcohol intake during fluvoxamine intake
• Psychotropic substances use during fluvoxamine intake
• Alteration of hepatic tests (ASAT, ALAT, GGT, BILI) more than 3x normal
• Glomerular filtration rate (GFR) \< 60 ml/min/1.73 m2
• Medical history of chronic alcoholism or abuse of psychoactive drugs
• Regular use of psychotropic substances
• Sensitivity to any of the drugs used
• Psychiatric disorders
• Beck Score ≥ 10 (question related to suicide \>0)

Sponsors & Collaborators

• University Hospital, Geneva: lead

Study Sites (1)

Geneva University Hospitals, HUG

Geneva, Switzerland

RECRUITING

MeSH Terms

Interventions

Voriconazole; Fluvoxamine; Tablets; Omeprazole

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Oximes; Hydroxylamines; Amines; Organic Chemicals; Dosage Forms; Pharmaceutical Preparations; 2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Pyridines; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Caroline Samer, Prof

  Division of Clinical Pharmacology and Toxicology, Department of Anesthesiology, Pharmacology, Intensive Care and Emergency Medicine, Geneva University Hospitals

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Youssef Daali, Prof

CONTACT

022395430; Youssef.daali@hcuge.ch

Kenza Abouir, PharmD

CONTACT

0788918021; kenza.abouir@unige.ch

Study Design

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

Model Details: The study will include 3 distinct CYP2C19 genotype groups that will constitute the 3 arms of the study. For each volunteer, the study will consist of 3 sessions. Same drugs will be administered to the 3 arms of the study.

Study Record Dates

• First Submitted: February 11, 2022
• First Posted: March 3, 2022
• Study Start: April 1, 2022
• Primary Completion: March 31, 2023
• Study Completion: August 31, 2023
• Last Updated: November 3, 2022

Record last verified: 2022-10

Data Sharing

• IPD Sharing: Will not share

Locations

CH (1)