Toxicokinetics of ethylene glycol during fomepizole therapy: Implications for management

Study objective: The elimination kinetics of ethylene glycol (EG) in human subjects treated with fomepizole (4-methylpyrazole) were analyzed to establ ish the efficacy of alcohol dehydrogenase (ADH) inhibition and to character ize elimination pathways. Methods: Drug concentration data from patients enrolled in the EG arm of th e Methylpyrazole for Toxic Alcohols trial, a prospective, multicenter, open -label trial of fomepizole, were analyzed and compared with published estim ates. Results: In 19 patients analyzed (EG concentrations of 3.5 to 211 mg/dL), e limination was first order during fomepizole monotherapy (half-life of 19.7 +/-1.3 hours) and was not affected by the presence of ethanol, The eliminat ion rate was significantly faster (half-life of <8.6+/-1.1 hours, P<.001) i n the absence of fomepizole and ethanol, EG elimination by the kidneys was directly proportional to remaining renal function as estimated by creatinin e clearance, with a fractional excretion of 25.5%+/-9.4%. Renal elimination and hemodialysis were the only significant routes of EG elimination as lon g as fomepizole concentrations were maintained well above 10 mu mol/L (EG/f omepizole molar ratio, <100:1). All patients with normal serum creatinine c oncentrations at the initiation of fomepizole treatment had rapid rates of renal elimination (half-life of 16.8+/-0.8 hours). Conclusion: At doses used, fomepizole effectively inhibits ADH-mediated met abolism of EG, Serum creatinine concentration at presentation and creatinin e clearance can be used to predict EG elimination during fomepizole therapy and can help determine which patients will require hemodialysis to expedit e EG elimination. An absolute EG concentration above 50 mg/dL should no lon ger be used as an independent criterion for hemodialysis in patients treate d with fomepizole.