Evaluation of hepatotoxicity with off-label oral-treatment doses of voriconazole for invasive fungal infections

Elizabeth Gorski, John S. Esterly, Michael Postelnick, Steven Trifilio, Michael Fotis, Marc H. Scheetz

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)184-189
Number of pages6
JournalAntimicrobial agents and chemotherapy
Volume55
Issue number1
DOIs
StatePublished - Jan 2011

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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