Background: Voriconazole (VRC) is a widely used broad-spectrum antifungal agent. Non-linear pharmacokinetics, polymorphism of cytochrome CYP2C19, drug interactions and hepatic dysfunction may result in inter- and intra-individual variations of VRC blood levels. We reported Serious Neurological Adverse Events (SNAE) probably associated with prolonged VRC overdosing (trough blood levels > 5.5 mg/L during >7 d) (ICAAC 2005, M-2164). This observation suggested that VRC dose adjustment based on monitoring of blood levels may help to prevent SNAE. Objective: To prospectively evaluate the utility of monitoring VRC blood levels for prevention of SNAE. Methods: VRC trough blood levels were measured by HPLC during the first week of therapy in 25 consecutive treatment courses during 2005. VRC dosing was adjusted if VRC trough blood levels were >5.5 mg/L. Clinical follow-up included surveillance for adverse events (NCI criteria). Occurrence of SNAE during VRC therapy in 2004 (no prospective dose adjustment based on VRC blood levels) and 2005 (prospective dose adjustment) was compared. Results: Indications for VRC therapy were aspergillosis (60%), candidiasis (16%), and suspected mycosis (24%). Median VRC dose was 4 mg/kg bid (range 1.3-5.7). Median number of VRC trough blood levels measurements/treatment course was 2.5 (range 1-5). Median days to first measurement after starting VRC therapy were 2 (2-7). Nine pts (37%) presented transient self-limiting visual disturbances/hallucinations. Two patients (8%) presented severe hepatotoxicity. Occurrence of SNAE in 2004 and 2005 is compared in table 1. Conclusions: These prospective data corroborate our preliminary report that rapid dose adjustment in patients with VRC blood levels exceeding 5.5 mg/L may help to prevent serious neurological adverse events. Further observations are needed to confirm this finding.
Full conference title:
16th European Congress of Clinical Microbiology and Infectious Diseases
- ECCMID 16th (2006)