Fosphenytoin Pharmacogenetics - Genetic Drug Testing Gene2Rx

Drug Overview

Fosphenytoin, marketed under the brand name Cerebyx, is an anticonvulsant prodrug of phenytoin. It is administered intravenously or intramuscularly to rapidly achieve therapeutic phenytoin concentrations in patients with acute seizure activity.

This medication is primarily used for the treatment and prevention of status epilepticus and for short-term seizure control when oral administration is not feasible. By converting to phenytoin in the bloodstream, fosphenytoin stabilizes neuronal membranes and reduces repetitive firing of action potentials.

The mechanism of action involves modulation of voltage-gated sodium channels in the central nervous system, decreasing the excitability of neurons and preventing the spread of seizure discharges.

Relevant Genes and Their Roles

The two genes most relevant to fosphenytoin response are CYP2C9 and HLA-B. CYP2C9 encodes a liver enzyme responsible for converting phenytoin into inactive metabolites. HLA-B is part of the immune system, and the HLA-B*15:02 variant is associated with a risk of severe cutaneous adverse reactions.

Variations in CYP2C9 can alter the rate of phenytoin metabolism, leading to higher or lower drug levels in the blood. HLA-B*15:02 does not affect metabolism but increases the risk of Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) in susceptible individuals.

Impact of Genetics on Drug Response

Genetic differences in CYP2C9 categorize patients into poor, intermediate, or normal metabolizers, which directly influences phenytoin clearance and risk of toxicity. Poor metabolizers have reduced enzyme activity, leading to elevated drug levels and greater toxicity risk, while intermediate metabolizers have modestly slower clearance. HLA-B*15:02 carriers face an increased risk of severe skin reactions regardless of metabolism status.

Expected Clinical Effects of Genetic Variation

Ultra-rapid/Rapid Metabolizer

Effect on drug levels: Potentially increased clearance leading to lower plasma concentrations.
Clinical consequence: May not achieve therapeutic levels with standard dosing.
Side effects: Lower risk of phenytoin toxicity; possible subtherapeutic response and breakthrough seizures.

Normal Metabolizer

Effect on drug levels: Expected drug levels within the target range using standard dosing.
Clinical consequence: Typical seizure control with regular monitoring.
Side effects: Standard risk profile for phenytoin, including dose-related central nervous system effects.

Intermediate Metabolizer

Effect on drug levels: Mildly reduced metabolism leading to slightly higher drug concentrations.
Clinical consequence: Generally maintain standard dosing; monitor levels.
Side effects: Slightly increased risk of dose-related side effects if not monitored.

Poor Metabolizer

Effect on drug levels: Significantly reduced clearance causing elevated plasma levels.
Clinical consequence: Higher risk of toxicity, such as sedation and ataxia.
Side effects: Increased frequency and severity of central nervous system adverse effects.

Indeterminate/Not Available

Effect on drug levels: Unknown
Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring

Dosing Guidelines

The following dosing guidelines are based on the available guidelines for fosphenytoin from CPIC.

CYP2C9 Dosing Guideline

Phenotype	Clinical Consequence	Guideline Recommendation
Normal Metabolizer	Your body processes the drug normally; you can follow the usual dosing with monitoring.	No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to standard practice.
Intermediate Metabolizer (AS 1.5)	Your body slows the drug slightly, but no dose changes are usually needed.	No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to standard practice.
Intermediate Metabolizer (AS 1)	Your body slows the drug more, so maintenance doses should be reduced by about a quarter after the first dose.	For first dose, use typical initial or loading dose. For subsequent doses, use ~25% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to standard practice.
Poor Metabolizer (AS 0.5)	Your body processes the drug very slowly, so maintenance doses should be cut in half after the first dose.	For first dose, use typical initial or loading dose. For subsequent doses, use ~50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to standard practice.
Poor Metabolizer (AS 0)	Your body processes the drug very slowly, so maintenance doses should be cut in half after the first dose.	For first dose, use typical initial or loading dose. For subsequent doses, use ~50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to standard practice.
Indeterminate	The impact of your genotype on response to this drug is unknown.	Initiate therapy with recommended starting dose.
Not available	The impact of your genotype on response to this drug is unknown.	Initiate therapy with recommended starting dose.

Alternative Treatment Options

CPIC guidelines do not specify alternate drugs for fosphenytoin. Clinicians may consider other antiseizure agents such as levetiracetam or valproate when dosing adjustments are not feasible or in cases of high-risk genotypes.

Fosphenytoin