Inflammation altered correlation between CYP2C19 genotype and CYP2C19 activity in patients receiving voriconazole

Area of Science:

• Pharmacology
• Clinical Pharmacy
• Medical Mycology

Background:

• Voriconazole is crucial for treating and preventing fungal infections.
• CYP2C19 genotype correlates with voriconazole exposure in prophylaxis but not invasive aspergillosis.
• Proinflammatory cytokines can inhibit CYP2C19 activity, potentially causing phenoconversion.

Purpose of the Study:

• To investigate the relationship between inflammation, CYP2C19 genotype-predicted phenotype, and actual CYP2C19 activity in patients receiving voriconazole.

Main Methods:

• Utilized data from two prospective voriconazole treatment studies (NCT02074462, NCT00893555).
• Assessed CYP2C19 activity and inflammation using dose-corrected voriconazole plasma concentrations and C-reactive protein (CRP) levels, respectively.
• Analyzed data from 39 patients with paired voriconazole and CRP measurements.

Main Results:

• CYP2C19 genotype distribution: 31% intermediate (IM), 41% normal (NM), and 28% rapid metabolizers (RM).
• During inflammation, dose-corrected voriconazole levels increased significantly across all phenotypes (245% for NMs, 278% for IMs, 486% for RMs).
• Patients with high CRP (>50 mg/L) showed phenoconversion to a lower metabolizer phenotype, irrespective of their baseline CYP2C19 genotype.

Conclusions:

• Inflammation downregulates CYP2C19 activity, leading to increased voriconazole plasma concentrations.
• Phenoconversion to a lower metabolizer status occurs during inflammation, impacting voriconazole exposure.
• While the effect is most pronounced in rapid metabolizers, no clinically significant differences between CYP2C19 genotypes were observed in this context.