281: Serial Voriconazole Therapeutic Drug Monitoring in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation

Voriconazole is effective for prophylaxis and therapy of invasive fungal infections (IFI). It is metabolized by the CYP450 system 2C19, 2C9 and 3A4 isosenzymes. We have reported that significant interpatient variability exists in plasma voriconazole concentrations after allogeneic HSCT and that about 15% of patients have no detectable voriconazole in the plasma despite adequate dose (Trifilio et al. Cancer 2007;109:1532–1535). Low plasma levels have also been associated with decreased survival in patients with aspergillosis and increased breaktrough Candida glabrata infections (Trifilio et al. Bone Marrow Transplant 2007;40:451–456). Treatment or prophylaxis for IFIs after HSCT is prolonged, and changing conditions are likely to alter voriconazole pharmacokinetics which may predispose to treatment failure. We studied the relationship between the first and second voriconazole levels in 29 allogeneic HSCT recipients whose first plasma voriconazole level was adequate (>2 μg/mL). The first level was drawn 6 days after starting voriconazole (usually day +6 post-HSCT), and the second level was drawn at a variable time after the first (median 9 days; range 1–252 days). The majority of patients received the drug at the dose of 200 mg twice a day orally. The two levels were strongly correlated to each-other (r = 0.72; p < 0.0001), but not to the interval between the two (p < 0.6) or weight (p < 0.49). 10 patients had a level <2 μg/mL on the second measurement. Optimal discriminant analysis revealed that all 11 patients with an initial voriconazole level ≤4.6 μg/mL had a second level that was <2 μg/mL (p < 0.02). Neither the interval between the two levels (p < 0.15) or weight (p < 0.75) predicted whether a patient's second voriconazole level was <2 μg/mL. However, when the analysis was expanded to a total of 43 patients in whom the first level was ≥1 μg/mL, 10 of whom had a second level of <1 μg/mL, no factor could be found that could reliably predict for a second level of <1 μg/mL. These data suggest that serial plasma voriconazole levels can change in an unpredictable fashion over time after HSCT - sometimes decreasing to levels that may place the patient at risk for breakthrough IFIs. Patients who require prolonged voriconazole administration may benefit from ongoing therapeutic drug monitoring and dose adjustment.