Department of Pathology and Laboratory Medicine, School of Medicine, University of California, Davis, USA.
Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, USA.
J Burn Care Res. 2022 Sep 1;43(5):987-996. doi: 10.1093/jbcr/irac062.
Management of critically ill patients requires simultaneous administration of many medications. Treatment for patient comorbidities may lead to drug-drug interactions which decrease drug efficacy or increase adverse reactions. Current practices rely on a one-size-fits-all dosing approach. Pharmacogenetic testing is generally reserved for addressing problems rather than used proactively to optimize care. We hypothesized that burn and surgery patients will have one or more genetic variants in drug metabolizing pathways used by one or more medications administered during the patient's hospitalization. The aim of this study was to determine the frequency of variants with abnormal function in the primary drug pathways and identify which medications may be impacted. Genetic (19 whole exome and 11 whole genome) and medication data from 30 pediatric burn and surgery patients were analyzed to identify pharmacogene-drug associations. Nineteen patients were identified with predicted altered function in one or more of the following genes: CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The majority had decreased function, except for several patients with CYP2C19 rapid or ultrarapid variants. Some drugs administered during hospitalization that rely on these pathways include hydrocodone, oxycodone, methadone, ibuprofen, ketorolac, celecoxib, diazepam, famotidine, diphenhydramine, and glycopyrrolate. Approximately one-third of the patients tested had functionally impactful genotypes in each of the primary drug metabolizing pathways. This study suggests that genetic variants may in part explain the vast variability in drug efficacy and suggests that future pharmacogenetics research may optimize dosing regimens.
危重症患者的管理需要同时给予多种药物。针对患者合并症的治疗可能会导致药物-药物相互作用，从而降低药物疗效或增加不良反应。目前的治疗方法依赖于一刀切的剂量方案。药物基因组学检测通常仅用于解决问题，而不是主动用于优化治疗。我们假设烧伤和手术患者在住院期间使用的一种或多种药物的药物代谢途径中会有一个或多个遗传变异。本研究的目的是确定主要药物途径中具有异常功能的变异的频率，并确定哪些药物可能受到影响。对 30 名儿科烧伤和手术患者的遗传（19 个全外显子和 11 个全基因组）和药物数据进行了分析，以确定药物基因-药物关联。19 名患者被确定在以下一个或多个基因中具有预测的功能改变：CYP2C9、CYP2C19、CYP2D6 和 CYP3A4。大多数患者的功能降低，除了几个 CYP2C19 快速或超快变异的患者。在住院期间使用的一些依赖这些途径的药物包括氢可酮、羟考酮、美沙酮、布洛芬、酮咯酸、塞来昔布、地西泮、法莫替丁、苯海拉明和格隆溴铵。大约三分之一的患者在每个主要药物代谢途径中都有功能上有影响的基因型。本研究表明，遗传变异可能部分解释了药物疗效的巨大差异，并表明未来的药物遗传学研究可能优化剂量方案。
