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

Fohner, Alison E.a,,b,,c; Ranatunga, Dilrini K.a; Thai, Khanh K.a; Lawson, Brian L.a; Risch, Neild; Oni-Orisan, Akinyemid,,e; Jelalian, Aline T.f; Rettie, Allan E.g; Liu, Vincent X.a; Schaefer, Catherine A.a

doi: 10.1097/FPC.0000000000000383
Original Articles

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 and 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 with 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). Decreased function CYP2C9 genotypes were associated with medication dispensing patterns indicating dose decrease, use of alternative anticonvulsants, and worse adherence, although these associations varied by treatment indication for phenytoin.

Conclusion CYP2C9 variation was associated with clinically meaningful differences in clinician prescribing practice and patient response, with potential implications for healthcare utilization and treatment efficacy.

aDivision of Research, Kaiser Permanente Northern California, Oakland, California

bDepartment of Epidemiology

cInstitute of Public Health Genetics, University of Washington, Seattle, Washington

dInstitute of Human Genetics

eDepartment of Clinical Pharmacy, University of California San Francisco, San Francisco

fDepartment of Neurology, Kaiser Permanente Northern California, Walnut Creek, California

gDepartment of Medicinal Chemistry, University of Washington, Seattle, Washington, USA

Received 8 April 2019 Accepted 16 July 2019

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Correspondence to Alison E. Fohner, PhD, Department of Epidemiology, University of Washington, Seattle, WA 98195, USA, Tel: +206 685 2715; e-mail:

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