Fomepizole: a critical assessment of current dosing recommendations.
Fomepizole, 4-methylpyrazole (4-MP), is a competitive antagonist of alcohol dehydrogenase with a binding affinity >8000 times that of ethanol. The drug is currently labeled by the United States Food and Drug Administration for the treatment of adult patients with known or suspected ethylene glycol or methanol poisoning. Fomepizole's wide therapeutic dose range and safety profile confer several advantages over standard ethanol therapy for the treatment of toxic alcohol exposures, including the lack of ethanol-associated side effects. Published data and data obtained from the drug's manufacturer implies that the dose escalation after 48 hours is to compensate for fomepizole-induced increased body clearance resulting from autoinduction of the cytochrome P450 (CYP) drug metabolizing enzyme CYP2E1. However, we were unable to identify any evidence of fomepizole's metabolism occurring via CYP2E1 in humans while the data most frequently cited as evidence for induction do not appear to support this claim. Based on this data along with the apparent zero-order kinetics, the current dose increase recommendations may be unnecessary and considering the safety margin described for fomepizole, an extremely conservative constant higher dose administered every 12 hours would appear to assure efficacy and tolerability. Despite the evidence, dose changes should only be implemented after careful clinical trials.
Bestic
Michelle
M
Department of Pharmacology and Critical Care, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Blackford
Martha
M
Reed
Michael
M
D000328:Adult; D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors; D000818:Animals; D000931:Antidotes / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019392:Cytochrome P-450 CYP2E1 / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D019855:Ethylene Glycol / Q000506:poisoning; D000077604:Fomepizole; D006801:Humans; D000432:Methanol / Q000506:poisoning; D017410:Practice Guidelines as Topic; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
D000931:Antidotes; D011720:Pyrazoles; D000077604:Fomepizole; D000426:Alcohol Dehydrogenase; D019392:Cytochrome P-450 CYP2E1; D019855:Ethylene Glycol; D000432:Methanol