Phenoconversion Due to Drug-Drug Interactions in CYP2C19 Genotyped Healthy Volunteers

To compensate for drug response variability, drug metabolism phenotypes are determined based on the results of genetic testing, and if necessary, drug dosages are adjusted. In some cases, discrepancies between predicted and observed phenotypes (phenoconversion) may occur due to drug-drug interactions caused by concomitant medications. We conducted a prospective, exploratory study to evaluate the risk of CYP2C19 phenoconversion in genotyped healthy volunteers exposed to CYP2C19 inhibitors. Three groups of volunteers were enrolled: CYP2C19 g-RM, g-NM, and g-IM (g- for genetically predicted). All volunteers received as CYP2C19 phenotyping substrate 10 mg omeprazole (OME) alone at the control session and in co-administration with CYP2C19 inhibitors: voriconazole 400 mg and fluvoxamine 50 mg in second and third study sessions, respectively. Phenoconversion occurred in over 80% of healthy volunteers, with variations among genotypic groups, revealing distinct proportions in response to fluvoxamine and voriconazole. Statistically significant differences were observed in mean metabolic ratios between CYP2C19 intermediate metabolizers (g-IMs) with *1/*2 and *2/*17 genotypes, with the *2/*17 group exhibiting lower ratios, and distinctions were noted between genotypic groups, emphasizing the impact of genetic variations on drug metabolism. When reclassified according to CYP2C19 baseline-measured phenotype into p-RM, p-NM, and p-IM (p- for measured phenotype), we observed 100% phenoconversion of p-RMs and a significant phenotype switch in p-NMs, p-IMs, and p-PMs after fluvoxamine and voriconazole, and complete phenoconversion of p-IMs to p-PMs on both inhibitors, emphasizing the impact of genetic variations on the vulnerability to CYP2C19 phenoconversion and the importance of considering both genotyping and phenotyping in predicting drug response.