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

Healthy

Phenoconversion, Pharmakinetics, Genotype, Cytochrome 2C19

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.

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.

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