CPIC Guideline update: HLA-B/CYP2C9 and Phenytoin/Fosphenytoin

The 2020 CPIC Guideline update for HLA-B, CYP2C19 and phenytoin dosing is now published in Clinical Pharmacology and Therapeutics. The accepted article can be accessed on the PharmGKB page for phenytoin and on the CPIC website.

Phenytoin is an antiepileptic drug with inter-individual pharmacokinetic variability, partly due to CYP2C9 genetic variation, and  a narrow therapeutic index. The presence of the HLA-B*15:02 variant allele is associated with an increased risk of phenytoin-induced cutaneous adverse reactions of Stevens-Johnson syndrome and toxic epidermal necrolysis.

Literature published after the 2014 guideline was reviewed and the recommendations and supplemental information were updated. This includes updates to CYP2C9 allele assignments using the activity score (AS) system. The CYP2C9*2/*2 diplotype (AS=1) is now translated into the IM phenotype group (originally translated to PM). This is based on similar effects of CYP2C9*1/*3 (AS=1) and CYP2C9*2/*2 on metabolic ratio and dose requirements for multiple substrates. CYP2C9*3 is classified as ‘no function’ allele with an activity value of 0 for AS calculation.

For therapeutic recommendations and further details including an algorithm for suggested clinical actions based on HLA-B*15:02 and CYP2C9 genotype, please refer to the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C9 and HLA-B Genotypes and Phenytoin Dosing: 2020 Update.