Phenytoin Therapy and HLA-B*15:02 and CYP2C9 Genotypes

Phenytoin (brand name Dilantin) is an anticonvulsant medication used for the treatment of seizures (1).Phenytoin has a narrow therapeutic index—individuals that have supratherapeutic blood concentrations of phenytoin have increased risks of acute side effects. Dosing can be complex due to pharmacokinetic factors, including individual weight, age, gender, concomitant medications, plasma binding protein status, the presence of uremia or hyperbilirubinemia, and specific pharmacogenetic variants. As such, therapeutic drug monitoring is often used to adjust dose and maintain serum concentrations within the therapeutic range (10–20 μg/mL).The CYP2C9 enzyme is one of the main enzymes involved in the metabolism of phenytoin, and variant CYP2C9 alleles are known to influence phenytoin drug levels. Individuals who have decreased activity CYP2C9 variants may have reduced clearance rates of phenytoin and be at greater risk for dose-related side effects (2).An individual’s human leukocyte antigen B (HLA-B) genotype is a known risk factor for drug-induced hypersensitivity reactions. The HLA-B protein has an important immunological role in pathogen recognition and response, as well as to non-pathogens such as drugs. Individuals who have the HLA-B*15:02 allele are at high risk of developing potentially life-threatening phenytoin-induced Stevens-Johnson syndrome (SJS) and the related toxic epidermal necrolysis (TEN).The HLA-B*15:02 allele is most often found among individuals of Southeast Asian descent, where there is a strong association between SJS/TEN and exposure to carbamazepine. Carbamazepine is an antiseizure medication used to treat the same types of seizures as phenytoin, as well as trigeminal neuralgia and bipolar disorder.The FDA-approved drug label for phenytoin states that consideration should be given to avoiding phenytoin as an alternative for carbamazepine in individuals positive for HLA-B*15:02 (Table 1). The label also mentions that variant CYP2C9 alleles may contribute to unusually high levels of phenytoin (1).Dosing recommendations for phenytoin based on HLA-B and CYP2C9 genotype have also been published by the Clinical Pharmacogenetics Implementation Consortium (CPIC, Table 2, Figure 1) and the Dutch Pharmacogenetics Working Group (DPWG, Table 3, Table 4). These recommendations include the use of an antiseizure medication other than carbamazepine, phenytoin (or its prodrug fosphenytoin) for any HLA-B*15:02 positive individual regardless of CYP2C9 genotype, individual ancestry, or age. These recommendations also include specific dose reductions of phenytoin for individuals who have low or deficient enzyme activity (2, 3).