ANTIFUNGAL SELECTION

Voriconazole is an antifungal agent that is used for treatment or prophylaxis of certain fungal infections. Appropriate serum concentrations are critical for effective prevention or treatment of invasive fungal infections (IFIs) [52, 53]. Studies have demon- strated that subtherapeutic voriconazole trough concentrations have been strongly associated with therapeutic failure [54]. Importantly, up to 50% of patients receiving the standard pro- phylactic dose of 200 mg twice daily remain subtherapeutic at steady state [55]. There is a significant association between IFI- related mortality and subtherapeutic initial trough concentra- tions—even when therapeutic blood level monitoring is used to direct subsequent dosing [52, 53, 56].

Importantly, CYP2C19 is responsible for the majority of voriconazole metabolism; thus, polymorphisms in this gene can have a significant effect on serum concentrations [57]. The patients at greatest risk of inadequate drug concentra- tions and thus voriconazole failure are those with rapid CYP2C19 metabolism, which occurs in up to 30%–35% of whites and blacks, such that the drug is removed from the bloodstream too quickly and can never reach therapeutic lev- els [54, 58–65]. Preliminary data show that, in a population of stem cell transplant patients, genotype-guided dosing for vor- iconazole prophylaxis (higher initial doses for CYP2C19 rapid and ultrarapid metabolizers) resulted in zero cases of subther- apeutic initial trough concentrations in this subset of patients compared with 80% in historical controls (p< .001) [66]. Another study showed reduced overall costs with genotype- directed dosing for patients with AML, even when including the tests of genomic analysis [67]. Currently, CPIC recom- mends that patients with rapid, ultrarapid, or poor metabo- lism at CYP2C19 should avoid voriconazole in favor of an alternative antifungal