Optimization of voriconazole therapy for treatment of invasive aspergillosis: Pharmacogenomics and inflammatory status need to be evaluated.

Aims: Cytochrome 2C19 genotype-directed dosing of voriconazole (VRC) reduces the incidence of insufficient VRC trough concentrations (C ) but does not account for CYP3A polymorphisms, also involved in VRC metabolism. This prospective observational study aimed to evaluate the utility of a genetic score combining CYP2C19 and CYP3A genotypes to predict insufficient initial VRC C (<1 mg/L).

Methods: The genetic score was determined in hematological patients treated with VRC. The higher the genetic score, the faster the metabolism of the patient. The impact of the genetic score was evaluated considering initial VRC C and all VRC C (n = 159) determined during longitudinal therapeutic drug monitoring.

Results: Forty-three patients were included, of whom 41 received VRC for curative indication. Thirty-six patients had a genetic score ≥2, of whom 11 had an initial insufficient VRC C . A genetic score ≥2 had a positive predictive value of 0.31 for having an initial insufficient VRC C and initial VRC C was not associated with the genetic score. The lack of association between the genetic score and VRC C may be related to the inflammatory status of the patients (C-reactive protein [CRP] levels: median [Q1-Q3]: 43.0 [11.0-110.0] mg/L), as multivariate analysis performed on all VRC C identified CRP as an independent determinant of the VRC C adjusted for dose (P < .0001).

Conclusion: The combined genetic score did not predict low VRC exposure in patients with inflammation, which is frequent in patients with invasive fungal infections. Strategies for the individualization of VRC dose should integrate the inflammatory status of patients in addition to pharmacogenetic variants.