Voriconazole therapy and CYP2C19 phenotype: identifying patients who may need alternative antifungal therapy

CYP2C19 phenotype is a known contributor to the interpatient variability in voriconazole response. Alternative therapy is recommended for ultrarapid/rapid and poor metabolizers due to increased probability of subtherapeutic exposure and side effects, respectively. We aimed to evaluate whether CYP2C19 phenotype is associated with switching from voriconazole to alternative antifungal therapy, in settings where genetic results were not available at the time prescribing decisions were made.

A multicentre, retrospective observational study was conducted in three Australian hospitals. Patients who had previously taken voriconazole (from 1 May 2019 to 31 May 2024) were invited to undergo pharmacogenomic testing. Medical records were audited to compare switching decisions across patients with different CYP2C19 phenotypes. Differences in voriconazole exposure and voriconazole-related adverse effects were also explored.

Among 194 patients, most were normal or intermediate metabolizers (69%); 21% were rapid, 7% ultrarapid, and 3% poor metabolizers (underpowered). Switching to alternative antifungal therapy (32%; 62/194) mainly occurred due to adverse effect incidence and was not associated with CYP2C19 phenotype (P = 0.9041). C-reactive protein levels were significantly higher in patients who switched therapy (P < 0.001). All ultrarapid metabolizers on standard voriconazole 400 mg/day had subtherapeutic concentrations and only those on higher doses (500-1200 mg/day) achieved therapeutic concentrations.

CYP2C19 phenotype was not predictive of switching, which is a multifactorial prescribing decision likely influenced by therapeutic drug monitoring, inflammation and clinical status. Our observations on voriconazole dosing and exposure support a complementary prescribing approach: pharmacogenomic testing to identify patients who require atypical voriconazole dosing regimens and subsequent therapeutic drug monitoring to guide dose adjustments.