Voriconazole therapeutic drug monitoring in allogeneic hematopoietic stem cell transplant recipients

Voriconazole, a new antifungal agent, is increasingly being used after HSCT. The hepatic cytochrome P450 isoenzyme 2C19 plays a significant role in voriconazole metabolism. As CYP2C19 exhibits significant genetic polymorphism, some patients metabolize voriconazole poorly resulting in increased plasma drug levels. The clinical significance of this is unknown, and the utility of monitoring voriconazole levels is unclear. Steady- state trough plasma voriconazole levels were obtained in 25 allogeneic HSCT recipients using an HPLC assay. Patients had drug levels checked once ( n = 13), twice ( n = 10), or greater than or equal to3 times ( n = 2) 5 - 18 days ( median 10) after starting voriconazole or dose modi. cation. The 41 voriconazole levels were 0.2 - 6.8 mug/ ml ( median 1.6); 6 ( 15%) were < 0.5( p ossibly below the in vitro MIC90 for Aspergillus spp.). Voriconazole concentrations correlated with aspartate aminotranferase ( AST) ( r = 0.5; P = 0.0009) and alkaline phosphatase ( r = 0.34; P = 0.03), but not with creatinine, bilirubin and alanine aminotransferase ( ALT). Since liver dysfunction is common after HSCT, it was not possible to determine if elevated AST and alkaline phosphatase levels were the cause or the consequence of higher voriconazole levels. We conclude that trough voriconazole levels vary considerably between patients, and suggest monitoring levels in patients receiving voriconazole for confirmed fungal infections, and in those with elevated AST or alkaline phosphatase levels.