Oral administration of fomepizole produces similar blood levels as identical intravenous dose

Abstract

Introduction. Fomepizole is available intravenously (IV) for the treatment of methanol and ethylene glycol poisoning. Few studies demonstrate that fomepizole achieves effective serum concentrations after IV or oral (PO) use. The objective was to describe the comparative pharmacokinetics of fomepizole after a single PO and IV dose. Methods. This was a prospective, randomized, crossover trial in 10 healthy volunteers. Each received 15 mg/kg fomepizole, PO and by 30 minute IV infusion. Serum was collected at 0, 0.25, 0.5, 1, 2, 4, 7, 12, 24, 36, and 48 hours (h) and stored at −70°C. Candidate models were fit to the IV and PO data, simultaneously, using iterative 2-stage analysis weighted by the estimated inverse observation variance. Time above the MEC (T>MEC) was determined by numeric integration of the fitted functions using 10 μmoles/L as the minimum effective concentration (MEC). Results. Seven females and 3 males were enrolled. Sole complaints included headache and dizziness in 3 subjects and 10/10 reported an unpleasant taste. The final PK model was 2-compartment with 0-order IV and 1st-order PO input (following a fitted TLag) and Michaelis-Menten elimination. PO fomepizole was rapidly absorbed with a bioavailability of ∼100%. The Km was 0.935 ± 0.98 μmoles/L and the Vmax was 18.57 ± 9.58 μmoles/L/h. T>MEC was 32 h with agreement between PO and IV dosing. Conclusions. This is the first study that effectively determines a human Vmax and Km for PO and IV fomepizole. PO and IV administration of fomepizole result in similar pharmacokinetic parameters.