Risk of CYP2C19 Phenoconversion in Healthy Volunteers With Rapid, Normal, and Intermediate Predicted Metabolizers' Status (Switch19)

Impact of Genetic Polymorphism on Drug Interactions Involving CYP2C19: Risk of Phenoconversion in Healthy CYP2C19 Fast, Normal and Intermediate Metabolizers Status

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.

Study Overview

• Status: Recruiting
• Conditions: Healthy
• Intervention / Treatment: Drug: Voriconazole 200mg; Drug: FluvoxaMINE 50 Mg Oral Tablet; Drug: Omeprazole 10 MG Oral Tablet

Detailed Description

Phase 1, open-label, parallel study in healthy volunteers selected according to their genotypic belonging to one of the three study groups.

Volunteers are included in the study and go through a buccal swab for genotyping, allowing their allocation into 3 groups according to their CYP2C19 genotype (RM: *1/*17 - NM: *1/*1 - IM: *1/*2 and *2/*17).

Following this step, volunteers have an inclusion session to determine if they meet the inclusion and non-exclusion criteria for the study.

The included volunteers will participate in three study sessions will take place.

Session 1 (control session): administration of 10mg of omeprazole for CYP2C19 phenotyping Session 2: same as session 1 with a prior intake of voriconazole 400 mg (weak inhibitor of CYP2C19 2 hours before omeprazole intake) Session 3: same as session 1 with a prior intake of fluvoxamine (strong CYP2C19 inhibitor, 12 h before and 2 h before taking the omeprazole)

At each session, dried blood spot (DBS) samples will be collected before the intake of the omeprazole (T0) and then at 2, 3, 6 and 8 hours after taking the capsule.

A wash-out period of minimum 3 days will be observed between session 1 and 2 and of minimum 1 week will be observed between sessions 2 and 3.

• Study Type: Interventional
• Enrollment (Anticipated): 45
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Youssef Daali, Prof; Phone Number: 022395430; Email: Youssef.daali@hcuge.ch
• Study Contact Backup: Name: Kenza Abouir, PharmD; Phone Number: 0788918021; Email: kenza.abouir@unige.ch

Study Locations

• Switzerland
  • Genève, Switzerland
    • Recruiting
    • Geneva University Hospitals, HUG
    • Contact: Caroline Samer, Dr; Email: caroline.samer@hcuge.ch
    • Contact: Kenza Abouir; Email: kenza.abouir@hcuge.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• Participation in any other interventional clinical study within 3 months prior to inclusion
• 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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CYP2C19 Rapid Metabolizers (RM); CYP2C19 rapid metabolizers (RM) are characterized by one normal function allele and one increased function allele	Drug: Voriconazole 200mg; 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.; Other Names: J02AC03; Drug: FluvoxaMINE 50 Mg Oral Tablet; 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.; Other Names: N06AB08; Drug: Omeprazole 10 MG Oral Tablet; Omeprazole is a CYP2C19 probe substrate. It is used in the study as a tool for CYP2C19 phenotyping at each of the sessions.; Other Names: A02BC01
Experimental: CYP2C19 Normal metabolizers (NM); CYP2C19 normal metabolizers (NMs) harboring two normal function alleles defined by the lack of any characterized polymorphisms.	Drug: Voriconazole 200mg; 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.; Other Names: J02AC03; Drug: FluvoxaMINE 50 Mg Oral Tablet; 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.; Other Names: N06AB08; Drug: Omeprazole 10 MG Oral Tablet; Omeprazole is a CYP2C19 probe substrate. It is used in the study as a tool for CYP2C19 phenotyping at each of the sessions.; Other Names: A02BC01
Experimental: CYP2C19 Intermediate metabolizers (IM); 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; 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.; Other Names: J02AC03; Drug: FluvoxaMINE 50 Mg Oral Tablet; 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.; Other Names: N06AB08; Drug: Omeprazole 10 MG Oral Tablet; Omeprazole is a CYP2C19 probe substrate. It is used in the study as a tool for CYP2C19 phenotyping at each of the sessions.; Other Names: A02BC01

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC assessment	Test drugs and their metabolite AUC measurement in whole capillary blood as well as metabolite /probe AUC ratio and single points metabolic ratios.	1 year
CL assessment	Test drugs and their metabolite Cl measurement in whole capillary blood	1 year
Cmax assessment	Test drugs and their metabolite Cmax measurement in whole capillary blood	1 year
Tmax assessment	Test drugs and their metabolite Tmax measurement in whole capillary blood	1 year

Collaborators and Investigators

• Sponsor: University Hospital, Geneva
• Investigators: Principal Investigator: Caroline Samer, Prof, Division of Clinical Pharmacology and Toxicology, Department of Anesthesiology, Pharmacology, Intensive Care and Emergency Medicine, Geneva University Hospitals

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2022
• Primary Completion (Anticipated): March 31, 2023
• Study Completion (Anticipated): August 31, 2023

Study Registration Dates

• First Submitted: February 11, 2022
• First Submitted That Met QC Criteria: February 21, 2022
• First Posted (Actual): March 3, 2022

Study Record Updates

• Last Update Posted (Actual): November 3, 2022
• Last Update Submitted That Met QC Criteria: October 31, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Genotype; Phenoconversion; Pharmakinetics; Cytochrome 2C19
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Central Nervous System Depressants; Enzyme Inhibitors; Gastrointestinal Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Tranquilizing Agents; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Anti-Anxiety Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; Anti-Ulcer Agents; Proton Pump Inhibitors; 14-alpha Demethylase Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Omeprazole; Fluvoxamine; Voriconazole
• Other Study ID Numbers: 2022-XXXX

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No