Voriconazole Pharmacokinetics and Therapeutic Drug Monitoring: A Multi-Center Study

ABSTRACT

Voriconazole is a first line agent in the treatment of many invasive fungal infections and is known to display highly variable pharmacokinetics. Previous studies of voriconazole therapeutic drug monitoring (TDM) have suggested concentration monitoring to be clinically useful but have been limited by small patient samples at a single institution. This multi-center retrospective study aimed to investigate relationships between voriconazole concentration and clinical outcomes and adverse events, and assess clinical factors and drug interactions that may affect voriconazole concentration. Medical records were reviewed for patients who received voriconazole and had ≥1 concentration measured at seven hospitals in Australia. The study included 201 patients with 783 voriconazole trough concentrations. Voriconazole concentrations <1.7 mg/L were associated with a significantly greater incidence of treatment failure (19/74 patients [26%]) than at concentrations ≥1.7 mg/L (6/89 patients [7%] p<0.01). Neurotoxic adverse events (visual and auditory hallucinations) occurred more frequently at voriconazole concentrations >5 mg/L (10/31 patients [32%]) than at concentrations ≤5 mg/L (2/170 patients [1.2%] p<0.01). Multiple regression analysis of voriconazole concentration identified associations between increasing patient weight, oral administration of voriconazole and co-administration of phenytoin or rifampicin with significantly reduced concentrations, with increasing patient age and co-administration of proton pump inhibitors associated with increased concentrations. Co-administration of glucocorticoids was found to significantly reduce voriconazole concentrations, inferring a previously unreported drug interaction between glucocorticoids and voriconazole.