Evaluation of hepatotoxicity with off-label oral-treatment doses of voriconazole for invasive fungal infections.
The approved treatment dose of intravenous voriconazole is a weight-based dose of 4 mg/kg of body weight twice daily; the approved oral dosing is fixed at 200 mg twice daily. In our institution, patients frequently receive oral high-dose voriconazole at 4 mg/kg twice daily. It is unknown if higher doses are associated with increased hepatotoxicity. A retrospective cohort study of patients treated with oral voriconazole for presumed invasive fungal infection for ≥7 days was completed. Patients receiving a fixed dose (i.e., labeled dose) were frequency matched and compared to those receiving a weight-based dose (i.e., high dose). The primary endpoint of hepatotoxicity was evaluated by using NCI Common Terminology Criteria (CTC) and components of liver enzymes measuring >3× the upper limit of normal (ULN) and >5× baseline measurements. Secondary endpoints included an incidence of other adverse drug events. Twenty-five labeled-dose and 84 high-dose voriconazole patients were studied. Liver enzyme abnormalities were similar between groups, with the exception of labeled-dose patients experiencing more alkaline phosphatase (ALP) CTC >2× the baseline (P = 0.02) and ALP levels >3× the ULN (P = 0.02). Treatment with high dose was associated with the discontinuation of voriconazole for practitioner attribution of adverse drug events (P = 0.03), although reasons varied and no commonality of biomarker abnormality was identified. Multivariate analysis revealed that the duration of therapy and higher mg/kg total daily doses as interval variables were predictive of some hepatotoxicity outcomes. No difference existed in liver abnormalities for high-dose voriconazole; however, higher mg/kg doses and a longer duration of therapy may be associated with hepatotoxicity.
Department of Pharmacy, Northwestern Memorial Hospital, Chicago, Illinois, USA.
Elizabeth
E
Gorski
John S
JS
Esterly
Michael
M
Postelnick
Steven
S
Trifilio
Michael
M
Fotis
Marc H
MH
Scheetz
D000368:Aged; D000935:Antifungal Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D009181:Mycoses / Q000188:drug therapy*; D011743:Pyrimidines / Q000009:adverse effects* / Q000627:therapeutic use*; D012189:Retrospective Studies; D014230:Triazoles / Q000009:adverse effects* / Q000627:therapeutic use*; D065819:Voriconazole
D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole