Oral administration of fomepizole produces similar blood levels as identical intravenous dose.
BACKGROUND
Fomepizole is available intravenously (i.v.) for the treatment of methanol and ethylene glycol poisoning. Few studies demonstrate that fomepizole achieves effective serum concentrations after i.v. or oral (p.o.) use. The objective was to describe the comparative pharmacokinetics of fomepizole after a single p.o. and i.v. dose.


METHODS
This was a prospective, randomized, crossover trial in 10 healthy volunteers. Each received 15 mg/kg fomepizole, p.o. and by 30 minute i.v. 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 degrees C. Candidate models were fit to the i.v. and p.o. 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 micromoles/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 i.v. and 1(st)-order p.o. input (following a fitted TLag) and Michaelis-Menten elimination. p.o. fomepizole was rapidly absorbed with a bioavailability of approximately 100%. The Km was 0.935+/-0.98 micromoles/L and the Vmax was 18.57+/-9.58 micromoles/L/h. T>MEC was 32 h with agreement between p.o. and i.v. dosing.


CONCLUSIONS
This is the first study that effectively determines a human Vmax and Km for p.o. and i.v. fomepizole. p.o. and i.v. administration of fomepizole result in similar pharmacokinetic parameters.
Marraffa
Jeanna
J
Department of Emergency Medicine, SUNY Upstate Medical University, Syracuse, New York 13210, USA. marraffj@upstate.edu
Forrest
Alan
A
Grant
William
W
Stork
Christine
C
McMartin
Kenneth
K
Howland
Mary Ann
MA
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000931:Antidotes / Q000008:administration & dosage* / Q000378:metabolism* / Q000493:pharmacokinetics; D001682:Biological Availability; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D000077604:Fomepizole; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D011720:Pyrazoles / Q000008:administration & dosage* / Q000097:blood* / Q000493:pharmacokinetics
D000931:Antidotes; D011720:Pyrazoles; D000077604:Fomepizole