Magavern Emma F, Megase Maia, Thompson Jack, Marengo Gabriel, Jacobsen Julius, Smedley Damian, Caulfield Mark J
William Harvey Research Institute, Queen Mary University of London, London, United Kingdom.
Department of Clinical Toxicology and General Medicine, St Thomas' Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.
PLoS Med. 2025 Mar 27;22(3):e1004565. doi: 10.1371/journal.pmed.1004565. eCollection 2025 Mar.
Adverse drug reactions (ADRs) harm patients and are costly for healthcare systems. Genetic variation contributes to variability in medication response and prospective knowledge of these variants can decrease risk of ADRs, as shown in the PREPARE trial. Reduction in ADRs would affect only those reactions to drugs contained in well-validated pharmacogene-drug pairs. The scope of ADRs represented by these drugs on a population scale is unclear. The objective of this study was to characterize the pharmacogene-drug-associated ADR reporting landscape from a national regulatory pharmacovigilance dataset to elucidate the scale of potential ADR mitigation by pharmacogenomics (PGx) implementation.
All publicly available Yellow Card ADR reports to the United Kingdom Medicines and Healthcare Products Regulatory Agency, from 1963 to 2024, were compiled using programmatic data extraction. The ADRs were analysed with descriptive statistics, stratified by PGx status and by associated genes. Prescribing prevalence from the literature was compared with age range matched ADR reports for PGx-associated drugs. There were 1,345,712 ADR reports, attributed to 2,499 different substances. 115,789 adverse drug reports (9%) were associated with drugs for which ADR risk can be modified based on pharmacogenomic prescribing guidance. Seventy-five percent of these (n = 87,339) were due to medicines which interact with only three pharmacokinetic pharmacogenes (CYP2C19, CYP2D6, SLCO1B1). Forty-seven percent of all the PGx mitigatable ADRs identified were attributed to psychiatric medications (n = 54,846), followed by 24% attributed to cardiovascular medications (n = 28,279). Those experiencing PGx mitigatable ADRs, as compared with non-PGx mitigatable ADRs, were older and the ADRs more often consisted of severe non-fatal reactions. Many PGx-associated psychiatric drug ADRs were overrepresented as compared with prescribing prevalence, but fatal cardiac arrhythmias were uncommon consequences, comprising only 0.4% of these ADRs (n = 172 of n = 48,315 total ADRs). Limitations of this data source include under reporting of ADRs and reporting bias. These findings are based on analysis of the Yellow Card dataset described and may not represent all ADRs from a generalised patient population.
Nine percent of all reported ADRs are associated with drugs where a genetic variant can cause heightened risk of an ADR and inform prescribing. A panel of only three pharmacogenes could potentially mitigate three in every four PGx modifiable ADRs. Based on our findings, Psychiatry may be the single highest impact specialty to pilot PGx to reduce ADRs and associated morbidity, mortality and costs.
药物不良反应（ADR）对患者造成伤害，且给医疗系统带来高昂成本。基因变异导致药物反应存在差异，如PREPARE试验所示，对这些变异的前瞻性了解可降低ADR风险。ADR的减少仅会影响那些对经过充分验证的药物基因组 - 药物对中所含药物的反应。这些药物在人群层面所代表的ADR范围尚不清楚。本研究的目的是从国家监管药物警戒数据集中描述药物基因组 - 药物相关的ADR报告情况，以阐明实施药物基因组学（PGx）可能减轻ADR的规模。
使用程序化数据提取方法，汇编了1963年至2024年期间向英国药品和医疗产品监管局提交的所有公开可用的黄卡ADR报告。对ADR进行描述性统计分析，按PGx状态和相关基因进行分层。将文献中的处方流行率与PGx相关药物的年龄范围匹配的ADR报告进行比较。共有1,345,712份ADR报告，涉及2,499种不同物质。115,789份药物不良反应报告（9%）与可根据药物基因组学处方指南修改ADR风险的药物相关。其中75%（n = 87,339）是由于仅与三种药代动力学药物基因（CYP2C19、CYP2D6、SLCO1B1）相互作用的药物。所有确定的可通过PGx减轻的ADR中，47%归因于精神科药物（n = 54,846），其次24%归因于心血管药物（n = 28,279）。与不可通过PGx减轻的ADR相比，经历可通过PGx减轻的ADR的患者年龄更大，且这些ADR更常包括严重的非致命反应。与处方流行率相比，许多与PGx相关的精神科药物ADR的报告比例过高，但致命性心律失常是罕见的后果，仅占这些ADR的0.4%（在总共48,315份ADR中的n = 172份）。该数据源的局限性包括ADR报告不足和报告偏差。这些发现基于对所述黄卡数据集的分析，可能并不代表广大患者群体的所有ADR。
所有报告的ADR中有9%与基因变异可导致ADR风险增加并为处方提供参考的药物相关。仅一组三种药物基因就有可能减轻四分之三可通过PGx修改的ADR。根据我们的研究结果，精神科可能是试行PGx以减少ADR及相关发病率、死亡率和成本影响最大的单一专科。
