Aurantin Mechanism of Action

Pharmacologic Category: Antiepileptic (Hydantoin Derivative).
Pharmacology: Pharmacodynamics: Fosphenytoin is a prodrug intended for parenteral administration. Following parenteral administration, fosphenytoin is converted to its active metabolite, the anticonvulsant phenytoin. For every mmol of fosphenytoin sodium (Aurantin) administered, 1 mmol of phenytoin is produced. The pharmacological and toxicological effects of fosphenytoin sodium (Aurantin) include those of phenytoin. However, the hydrolysis of fosphenytoin to phenytoin yields two metabolites, phosphate and formaldehyde. Formaldehyde is subsequently converted to formate, which is in turn metabolized via a folate-dependent mechanism. Although phosphate and formaldehyde (formate) have potentially important biological effects, these effects typically occur at concentrations considerably in excess of those obtained when fosphenytoin sodium (Aurantin) is administered under conditions of use recommended in this labeling.
Mechanism of Action: Fosphenytoin is a prodrug of phenytoin and accordingly, its anticonvulsant effects are attributable to phenytoin.
After IV administration to mice, fosphenytoin blocked the tonic phase of maximal electroshock seizures at doses equivalent to those effective for phenytoin. In addition to its ability to suppress maximal electroshock seizures in mice and rats, phenytoin exhibits anticonvulsant activity against kindled seizures in rats, audiogenic seizures in mice, and seizures produced by electrical stimulation of the brainstem in rats. The cellular mechanisms of phenytoin thought to be responsible for its anticonvulsant actions include modulation of voltage dependent sodium channels of neurons, inhibition of calcium flux across neuronal membranes, modulation of voltage-dependent calcium channels of neurons, and enhancement of the sodium-potassium ATPase activity of neurons and glial cells. The modulation of sodium channels may be a primary anticonvulsant mechanism because this property is shared with several other anticonvulsants in addition to phenytoin.
Pharmacokinetics: Pharmacokinetics and Metabolism: Fosphenytoin sodium (Aurantin): Absorption/Bioavailability: When fosphenytoin sodium (Aurantin) is administered by IV infusion, maximum plasma fosphenytoin concentrations are achieved at the end of the infusion. Fosphenytoin has a half-life of approximately 15 minutes. Fosphenytoin is completely bioavailable following IM administration. Peak concentrations occur at approximately 30 minutes post-dose. Plasma fosphenytoin concentrations following IM administration are lower but more sustained than those following IV administration due to the time required for absorption of fosphenytoin from the injection site.
Distribution: Fosphenytoin sodium (Aurantin) is extensively bound (95% to 99%) to human plasma proteins, primarily albumin. Binding to plasma proteins is saturable with the result that the percent bound decreases as total fosphenytoin concentrations increase. Fosphenytoin displaces phenytoin from protein-binding sites. The volume of distribution of fosphenytoin increases with fosphenytoin sodium (Aurantin) dose and rate, and ranges from 4.3 to 10.8 L.
Metabolism and Elimination: The conversion half-life of fosphenytoin to phenytoin is approximately 15 minutes. The mechanism of fosphenytoin conversion has not been determined, but phosphatases probably play a major role. Fosphenytoin sodium (Aurantin) is not excreted in urine. Each mmol of fosphenytoin is metabolized to 1 mmol of phenytoin, phosphate, and formate (see General under Precautions).
Phenytoin (After Fosphenytoin sodium (Aurantin) Administration): In general, IM administration of fosphenytoin sodium (Aurantin) generates systemic phenytoin concentrations that are similar enough to oral phenytoin sodium to allow essentially interchangeable use.
The pharmacokinetics of fosphenytoin following IV administration of fosphenytoin sodium (Aurantin), however, is complex, and when used in an emergency setting (e.g., status epilepticus), differences in rate of availability of phenytoin could be critical. Studies have therefore empirically determined an infusion rate for fosphenytoin sodium (Aurantin) that gives a rate and extent of phenytoin systemic availability similar to that of a 50 mg/min phenytoin sodium infusion.
A dose of 15 to 20 mg PE/kg of fosphenytoin sodium (Aurantin) infused at 100 to 150 mg PE/min yields plasma-free phenytoin concentrations over time that approximate those achieved when an equivalent dose of phenytoin sodium (e.g., parenteral phenytoin) is administered at 50 mg/min (see Dosage & Administration).
Following administration of single IV fosphenytoin sodium (Aurantin) doses of 400 to 1200 mg PE, mean maximum total phenytoin concentrations increase in proportion to dose, but do not change appreciably with changes in infusion rate. In contrast, mean maximum unbound phenytoin concentrations increase with both dose and rate.
Absorption/Bioavailability: Fosphenytoin is completely converted to phenytoin following IV administration, with a half-life of approximately 15 minutes. Fosphenytoin is also completely converted to phenytoin following IM administration and plasma total phenytoin concentrations peak in approximately 3 hours.
Phenytoin has an apparent volume of distribution of 0.6 L/kg and is highly bound (90%) to plasma proteins, mainly albumin. Free phenytoin levels may be altered in patients whose protein-binding characteristics differ from normal. In the absence of fosphenytoin, approximately 12% of total plasma phenytoin is unbound over the clinically relevant concentration range. However, fosphenytoin displaces phenytoin from plasma protein-binding sites. This increases the fraction of phenytoin unbound (up to 30% unbound) during the period required for conversion of fosphenytoin to phenytoin (approximately 0.5 to 1 hour post infusion). Following administration of single IV fosphenytoin sodium (Aurantin) doses of 400 to 1200 mg PE, total and unbound phenytoin AUC values increase disproportionately with dose. Mean total phenytoin half-life values (12.0 to 28.9 hr) following fosphenytoin sodium (Aurantin) administration at these doses are similar to those after equal doses of parenteral phenytoin and tend to be greater at higher plasma phenytoin concentrations. The concentration of phenytoin in cerebrospinal fluid, brain, and saliva approximates the level of free phenytoin in plasma.
Metabolism and Elimination: Phenytoin is biotransformed in the liver by oxidative metabolism. The major pathway involves 4-hydroxylation, which accounts for 80% of all metabolites. CYP2C9 plays a major role in the metabolism of phenytoin (90% of net intrinsic clearance), while CYP2C19 has a minor involvement in this process (10% of net intrinsic clearance). This relative contribution of CYP2C19 to phenytoin metabolism may however increase at higher phenytoin concentrations.
Because the cytochrome systems involved in phenytoin hydroxylation in the liver are saturable at high serum concentrations, small incremental doses of phenytoin may increase the half-life and produce very substantial increases in serum levels when these are in or above the upper therapeutic range. The clearance of phenytoin has been shown to be impaired by CYP2C9 inhibitors such as phenylbutazone and sulfaphenazole. Impaired clearance has also been shown to occur in patients administered CYP2C19 inhibitors such as ticlopidine.
Most of the drug is excreted in the bile as inactive metabolites, which are then reabsorbed from the intestinal tract and eliminated in the urine partly through glomerular filtration, but more importantly via tubular secretion. Less than 5% of the dose is excreted as unchanged phenytoin.
Special Populations: Patients with Renal or Hepatic Disease: General under Precautions.
Age: The effect of age was evaluated in patients 5 to 98 years of age; however, no systematic studies in geriatric patients have been conducted. Patient age had no significant impact on fosphenytoin sodium (Aurantin) pharmacokinetics. Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20 to 30 years of age). Phenytoin dosing requirements are highly variable and must be individualized (see Dosing in Special Populations: Elderly Patients under Dosage & Administration).
Gender and Race: Gender and race have no significant impact on fosphenytoin or phenytoin pharmacokinetics.
Pediatrics: Pharmacokinetic data are available in pediatric patients from birth through 16 years of age. In these patients with status epilepticus who received loading doses of fosphenytoin sodium (Aurantin), the plasma fosphenytoin, total phenytoin, and unbound phenytoin concentration-time profiles did not signal any major differences from those in adult patients with status epilepticus receiving comparable doses.
Pharmacokinetic Interaction: Co-administration of nelfinavir tablets (1250 mg twice a day) with phenytoin capsule (300 mg once a day) did not change the plasma concentration of nelfinavir. However, co-administration of nelfinavir reduced the AUC values of phenytoin (total) and free phenytoin by 29% and 28%, respectively.
Toxicology: Preclinical Safety Data: Carcinogenesis: Carcinogenicity studies with fosphenytoin sodium (Aurantin) are unavailable. Since fosphenytoin is a prodrug of phenytoin, the carcinogenicity results with phenytoin can be extrapolated. In a transplacental and adult carcinogenicity study, phenytoin was administered in diet at 30 to 600 ppm to mice (4.5 to 90 mg/kg/day) and 240 to 2400 ppm (12 to 120 mg/kg/day) to rats. Hepatocellular tumors were increased at the higher doses in mice and rats. In additional studies, mice received 10, 25, or 45 mg/kg/day and rats were given 25, 50, or 100 mg/kg/day in the diet for 2 years. Hepatocellular tumors in mice increased at 45 mg/kg/day. No increases in tumor incidence were observed in rats. These rodent tumors are of uncertain clinical significance.
Genetic toxicity studies showed that fosphenytoin sodium (Aurantin) was not mutagenic in bacteria or in mammalian cells in vitro. It is clastogenic in vitro but not in vivo.