Source: Health Products and Food Branch (CA) Revision Year: 2017
Antizol (fomepizole) is a competitive inhibitor of alcohol dehydrogenase (ADH). Alcohol dehydrogenase catalyzes the oxidation of ethanol to acetaldehyde. Alcohol dehydrogenase also catalyzes the initial steps in the metabolism of ethylene glycol and methanol to their toxic metabolites.
Ethylene glycol, the main component of most antifreezes and coolants, is metabolized to glycoaldehyde, which undergoes subsequent sequential oxidations to yield glycolate, glyoxylate, and oxalate. Glycolate and oxalate are the metabolic by-products primarily responsible for the metabolic acidosis and renal damage seen in ethylene glycol toxicosis which presents with the following morbidities: nausea/vomiting, seizures, cardiac arrhythmias, stupor, coma, calcium oxaluria, acute tubular necrosis and death, depending on the amount of ethylene glycol ingested and the time elapsed since ingestion. The lethal dose of ethylene glycol in humans is approximately 1.4 mL/kg.
Methanol, the main component of windshield washer fluid, is slowly metabolized via alcohol dehydrogenase to formaldehyde with subsequent oxidation via formaldehyde dehydrogenase to yield formic acid. Formic acid is primarily responsible for the metabolic acidosis and visual disturbances (e.g., decreased visual acuity and potential blindness) associated with methanol poisoning. A lethal dose of methanol in humans is approximately 1-2 mL/kg.
Fomepizole has been shown in vitro and in vivo to block alcohol dehydrogenase enzyme activity in dog, monkey, and human liver. The relative affinity of fomepizole for human ADH is 80,000 times greater than that of methanol and ethylene glycol, and 8,000 times greater than that of ethanol (3, 18, 30). The concentration of fomepizole at which alcohol dehydrogenase is inhibited by 50% in vitro is approximately 0.1 mcmol/L. The plasma concentrations achieved in humans with the proposed dosage regimen are well above this, with peak concentrations of fomepizole between 100-300 mcmol/L (8.2-24.6 mg/L). These levels are achieved with oral or IV fomepizole doses of 10-20 mg/kg. Fomepizole is most effective when given in close proximity to the ethylene glycol or methanol ingestion before significant target organ damage occurs.
The plasma half-life of fomepizole varies with dose, even in patients with normal renal function, and has not been calculated.
After intravenous infusion, fomepizole rapidly distributes to total body water. The volume of distribution is between 0.6 L/kg and 1.02 L/kg.
In healthy volunteers, only 1-3.5% of the administered dose of fomepizole (7-20 mg/kg oral and IV) was excreted unchanged in the urine, indicating that metabolism is the major route of elimination. In humans, the primary metabolite of fomepizole is 4-carboxypyrazole (approximately 80-85% of administered dose), which is excreted in the urine. Other metabolites of fomepizole observed in the urine are 4-hydroxymethylpyrazole and the N-glucuronide conjugates of 4-carboxypyrazole and 4-hydroxymethylpyrazole.
After a single dose, the elimination of fomepizole is best characterized by Michaelis-Menten kinetics with saturable elimination occurring at plasma concentrations of 100-300 mcmol/L (8.2-24.6 mg/L).
With multiple doses, fomepizole rapidly induces its own metabolism via the cytochrome P450 mixed-function oxidase system, which produces a significant increase in the elimination rate after about 30-40 hours. After enzyme induction, elimination follows first-order kinetics.
No special pharmacokinetic studies have been performed with respect to pediatric, geriatric, hepatically-impaired, or renally-impaired patients.
Gender: Possible gender differences were not investigated therefore dose adjustments for patient subgroups cannot be recommended.
Fomepizole has been shown in vitro and in vivo to block alcohol dehydrogenase enzyme activity in dog, monkey, and human liver. The relative affinity of fomepizole for human ADH is 80,000 times greater than that of methanol and ethylene glycol, and 8,000 times greater than that of ethanol (3, 18, 30).
Fomepizole has been shown to inhibit ethylene glycol toxicity in rats (8), dogs (11, 17, 13), monkeys (9), and cats (12). Fomepizole has been shown to inhibit methanol toxicity in monkeys (4, 5, 24, 25, 26). Fomepizole is most effective when given in close proximity to the exposure of ethylene glycol or methanol, before significant renal damage or visual disturbance has occurred.
When used in sufficient doses, fomepizole inhibits the metabolism of ethylene glycol or methanol to their toxic metabolites and ameliorates metabolic acidosis before significant target organ damage develops in relevant animal models.
Animal and in vitro studies indicate that the main metabolite, 4-carboxypyrazole, is not active pharmacologically nor are any of the minor metabolites active at concentrations found following therapeutic doses of fomepizole.
In a study of dogs given a lethal dose of ethylene glycol, three animals each were administered fomepizole, ethanol, or left untreated (control group). The three animals in the untreated group became progressively obtunded, moribund, and died. At necropsy, all three dogs had severe renal tubular damage. Fomepizole or ethanol, given 3 hours after ethylene glycol ingestion, attenuated the metabolic acidosis and prevented the renal tubular damage associated with ethylene glycol intoxication.
Several studies have demonstrated that fomepizole plasma concentrations of approximately 10 mcmol/L (0.82 mg/L) in monkeys are sufficient to inhibit methanol metabolism to formate, which is also mediated by alcohol dehydrogenase. Based on these results, peak plasma concentrations of fomepizole in humans in the range of 100 to 300 mcmol/L (8.2-24.6 mg/L) have been targeted to assure adequate plasma concentrations for the effective inhibition of alcohol dehydrogenase.
An acute toxicology study has been conducted in the mouse and rat over the dose range of 0.75 to 2.00 g/kg. The oral LD50 (lethal dose, 50%) of fomepizole in the mouse and rat was 1.3 g/kg and 1.4 g/kg, respectively. The most pronounced toxic symptoms were hypnosis in high doses and sedation in low doses. Death occurred between 2 and 24 hours. One rat in the 1.75 g/kg dose group died between 24 and 48 hours post-dose.
However, in another study the oral LD50's of fomepizole were reported as 0.54 and 0.64 g/kg in the mouse and rat, respectively. The intravenous LD50 was reported to be 0.32 g/kg in both the mouse and the rat. These dose levels represent significant margins over those proposed in the human therapeutic dose regimen.
Based on a dose ranging study, fomepizole was evaluated for systemic toxicity in dogs following 14-days intravenous infusion at doses of 10, 20 and 30 mg/kg/day for 30 minutes every 12 hours. This infusion regimen is generally consistent with the planned label indication, but the duration of this study (14 days) exceeds the maximum therapeutic use in humans.
The results of this study indicated that such a regimen in dogs produces no signs of systemic toxicity or local vascular irritation at a dose of 10 mg/kg (no effect level) twice daily for 14 days. At 20 mg/kg, which is above the maximum planned clinical dose, effects were minimal and were limited to a decrease in serum triglycerides, an increase in serum sodium (males only), an increase in bicarbonate, and an increase in urine output (increased volume and decreased specific gravity). This dose of 20 mg/kg was considered a no-toxic-effect level in the dog. A dose of 30 mg/kg was a clear effect level, with the liver identified as the primary target organ (increased alkaline phosphatase and alanine transaminase (ALT), decreased triglycerides and increased liver weights). Also noted at this dose were decreased food consumption, decreased potassium, increased sodium and bicarbonate, and increased urine output. Even at this dose level, none of the effects were life threatening, and most (all except alkaline phosphatase and ALT) were reversible following a 28 day recovery period.
Plasma concentrations determined in this study indicate that, at the no effect level of 10 mg/kg, drug levels observed during the infusion were similar to those seen in humans.
The results of this study indicate that, under the planned conditions of clinical use and considering the short term use and life-saving potential of the drug, fomepizole is safe for the intended indication and does not represent a significant risk to the patient.
A series of experiments were conducted to evaluate the chronic toxicity in young male Cynomolgus monkeys. The objective of the first series of experiments was to assess the toxicity of fomepizole after dosing for six weeks in 12 monkeys. Toxicity assessments included clinical signs, hematology, and blood chemistry, and gross and microscopic pathology were evaluated.
Additionally, ophthalmoscopy with assessment of the fundus structures and recordings of the electroretinogram (ERG) were performed. The objective of the second series of experiments was to identify any direct effect of fomepizole on the eye of the monkey as assessed by ERG.
Except for one monkey who died during anesthesia, the administration of fomepizole induced no clinical toxic reactions, regardless of the dose administered and no visual disturbances were observed. The results of these experiments supported that an initial loading dose of fomepizole administered at a dose of 15-20 mg/kg inhibited methanol oxidation in the monkey model. Furthermore, it was concluded that the results of these experiments clearly indicated that fomepizole would be an attractive substitute for ethanol in the treatment of methanol poisoning.
There have been no long-term studies performed in animals to evaluate carcinogenic potential.
There was a positive Ames test result in the Escherichia coli tester strain WP2uvrA and the Salmonella typhimurium tester strain TA102 in the absence of metabolic activation using fomepizole concentrations of 100, 333, 1000, 3330, and 5000 mcg/plate.
In addition, the mutagenicity of fomepizole was tested in the in vivo mouse micronucleus assay. In the 35 animals tested, dosed at 75, 150, and 300 mg/kg, the bone marrow showed that fomepizole did not induce a significant increase in the frequency of micronucleated polychromatic erythrocytes; thus, this test did not indicate bone marrow cytotoxicity. The mutagenicity of fomepizole is considered to be negative in this assay.
In rats, fomepizole (110 mg/kg) administered orally for 40 to 42 days resulted in decreased testicular mass (approximately 8% reduction). This dose is approximately 0.6 times the human maximum daily exposure based on surface area (mg/m²). This reduction was similar for rats treated with either ethanol or fomepizole alone. When fomepizole was given in combination with ethanol, the decrease in testicular mass was significantly greater (approximately 30% reduction) compared to those rats treated exclusively with fomepizole or ethanol.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
