Assessing the clinical impact of CYP2C9 pharmacogenetic variation on phenytoin prescribing practice and patient response in an integrated health system
Assessing the clinical impact of CYP2C9 pharmacogenetic variation on phenytoin prescribing practice and patient response in an integrated health system
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DOI：
10.1097/fpc.0000000000000383
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发表时间：
2019-10-01
影响因子：
2.6
通讯作者：
Schaefer, Catherine A.
中科院分区：
文献类型：
--
作者：
Fohner, Alison E.;Ranatunga, Dilrini K.;Schaefer, Catherine A.
目的评估CYP 2C 9变异对苯妥英钠治疗中基因型未知患者的反应和临床处方的影响。方法回顾性分析1996年至2017年期间填写苯妥英处方的成人健康和老龄化队列参与者的遗传流行病学研究资源。我们使用实验室检查结果、药物分发记录和医疗记录来确定CYP 2C 9基因型与苯妥英血药浓度、神经系统副作用和药物分发模式（反映临床医生处方实践和患者反应）的相关性。结果在993名受试者中，我们根据CYP 2C 9基因型确定了69%的广泛代谢型，20%的高中间代谢型，10%的低中间代谢型和2%的慢代谢型。与快代谢基因型相比，低-中/慢代谢基因型与剂量调整后苯妥英血药浓度升高[21.3 pg/mL，95%可信区间（CI）：13.6-29.0 pg/mL; P < 0.01]和神经系统副作用风险增加相关（风险比：2.40，95%CI：1.24-4.64; P < 0.01）。功能降低的CYP 2C 9基因型与药物分配模式相关，表明剂量降低、使用替代抗惊厥药和依从性较差，尽管这些相关性因苯妥英治疗适应症而异。结论CYP 2C 9变异与临床医生处方实践和患者反应的临床有意义的差异相关，对医疗保健利用和治疗效果具有潜在意义。
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.