No abstract

Objective Voriconazole, a first line agent for the treatment of invasive fungal infections (IFIs), is metabolized by CYP2C19. A significant portion of patients fail to achieve therapeutic trough concentrations with standard weight-based voriconazole dosing, placing them at increased risk for treatment failure, which can be life threatening. We sought to test the association between CYP2C19 genotype and subtherapeutic voriconazole concentrations in adults with IFIs. Methods Adults receiving weight-based voriconazole dosing for the treatment of IFIs were genotyped for the CYP2C19*2, *3, and *17 polymorphisms, and CYP2C19 metabolizer phenotypes were inferred. Steady-state voriconazole trough plasma concentrations and the prevalence of subtherapeutic troughs (<2 mg/L) were compared between patients with the CYP2C19*17/*17 (ultrarapid metabolizers, UMs) or *1/*17 genotypes (rapid metabolizers, RMs) versus those with other genotypes. Logistic regression, adjusting for clinical factors, was performed to estimate the odds of subtherapeutic concentrations. Results Of 70 patients included (mean age 51±18 years), 39% were RMs or UMs. Compared to patients with the other phenotypes, RMs/UMs had a lower steady state trough concentration (4.26±2.2 vs. 2.86±2.3, p=0.0093), and a higher prevalence of subtherapeutic troughs (16% vs. 52%, p=0.0028), with an odds ratio of 5.6 (95% confidence interval 1.64–19.24, p=0.0059). Conclusion Our findings indicate that adults with the CYP2C19 RM or UM phenotype are more likely to have subtherapeutic concentrations with weight-based voriconazole dosing. These results corroborate previous findings in children and support potential clinical utility of CYP2C19 genotype-guided voriconazole dosing to avoid underexposure in RMs and UMs.