Assessing the clinical impact of CYP2C9 pharmacogenetic variation on phenytoin prescribing practice and patient response in an integrated health system

Abstract

Objective: To assess the impact of CYP2C9 variation on phenytoin patient response and clinician prescribing practice where genotype was unknown during treatment. Methods: A retrospective analysis of Resource on Genetic Epidemiology Research on Adult Health and Aging cohort participants who filled a phenytoin prescription between 1996-2017. We used laboratory test results, medication dispensing records, and medical notes to identify associations of CYP2C9 genotype with phenytoin blood concentration, neurologic side effects, and medication dispensing patterns reflecting clinician prescribing practice and patient response. Results: Among 993 participants, we identified 69% extensive, 20% high-intermediate, 10% low-intermediate, and 2% poor metabolizers based on CYP2C9 genotypes. Compared to extensive metabolizer genotype, low-intermediate/poor metabolizer genotype was associated with increased dose-adjusted phenytoin blood concentration (21.3 pg/mL, 95% confidence interval (CI): 13.6-29.0 pg/mL; p < 0.01) and increased risk of neurologic side effects (hazard ratio: 2.40, 95% CI: 1.24-4.64; p < 0.01). CYP2C9 genotypes were associated with medication dispensing patterns indicating dose decrease, use of alternative anticonvulsants, and worse adherence, though these associations varied by treatment indication for phenytoin.

Associations of CYP2C9 and CYP2C19 Pharmacogenetic Variation with Phenytoin‐Induced Cutaneous Adverse Drug Reactions

“…Interestingly, we did not observe significantly fewer cutaneous adverse events among men compared with women, although we previously identified fewer neurological side effects among men, perhaps due to average differences in volume of distribution. 19 Higher phenytoin blood concentrations due to reduced CYP2C9 activity may increase odds of toxicity directly, or perhaps by increasing flux through alternative pathways that form toxic metabolites. Both CYP2C9 and CYP2C19 catalyze initial formation of p-hydroxy phenytoin, which may be further oxidized to a catechol that is the precursor to a highly reactive o-quinone known to form drug-protein adducts.…”

“…Using outpatient medication dispensing records, we identified members of the GERA cohort who filled at least one prescription for phenytoin as an outpatient between January 1, 1996 and September 1, 2017, as described elsewhere. 19 For this study, we considered only participants who filled their first phenytoin prescription after January 1, 2005, when clinical notes containing visit details and free text became embedded in the EHR. We extracted all instances of phenytoin dispensing in an outpatient setting, including date, and daily dose.…”

“…Genotyping DNA collection and genotyping are described elsewhere for both HLA-B and CYP2C9. 19,28 Table S1 presents the rs numbers and alleles used to identify CYP2C9 alleles, which included *2, *3, *5, *8, *11, and *12. We tested for all variants for Hardy-Weinberg using the exact test.…”

“…11 In addition, cytochrome P450 (CYP) 2C9*2 and CYP2C9*3 alleles are known to reduce CYP2C9 enzyme activity. 2,4,[12][13][14][15][16][17][18][19] These variants decrease phenytoin metabolism and increase both phenytoin blood concentrations and risk for neurological toxicities. Accordingly, CPIC and the Royal Dutch Pharmacists Association -Pharmacogenetics Working Group (DPWG) recommend reducing the starting dose of phenytoin for patients with CYP2C9 genotypes that predict reduced enzyme function.…”

Emerging strategies to bridge the gap between pharmacogenomic research and its clinical implementation

“…Similarly, in a study of 993 patients it was concluded that the dose-adjusted phenytoin blood concentrations were higher and the risk for neurologic side effects was elevated by 2.4-fold among carriers of reduced function CYP2C9 alleles. 58 A similar retrospective approach has been applied in many studies from different countries regarding the relative importance of VKORC1 and CYP2C9 genotypes for warfarin maintenance doses. 59 Indeed, a multitude of dosing algorithms have been developed in different countries for such predictions.…”