Clinical importance of the drug interaction between statins and SYP3A inhibitors

描述(由申请人提供)：国家胆固醇教育计划(NCEP)指南建议在包括糖尿病患者和老年人(65岁)在内的高危患者中积极降低胆固醇。尽管他汀类药物是非常安全的药物，但它们有可能出现轻微和严重的不良反应，特别是在服用伴随药物延长他汀类药物暴露的患者时。具体目的：比较同时使用CYP3A4底物他汀类药物[阿托伐他汀或辛伐他汀]和CYP3A4抑制剂的肌病和急性肾损伤的相对发生率与联合使用非3A4底物他汀类药物[氟伐他汀、普伐他汀或瑞舒伐他汀]和CYP3A4抑制剂后肌病和急性肾损伤的发生率。背景和意义：他汀类药物和抑制细胞色素P3A4同工酶的药物的潜在有害组合经常被使用。这一点尤其重要，因为阿托伐他汀和辛伐他汀通过细胞色素P450 3A4同工酶进行氧化代谢。同时使用CYP3A4底物他汀类药物(阿托伐他汀和辛伐他汀)和CYP3A4抑制剂会增加他汀类药物的暴露，并有可能增加他汀类药物相关的不良事件。考虑到与CYP3A4抑制剂同时服用可能会增加他汀类药物的暴露和相关的他汀类药物不良事件，我建议通过进行一项病例队列研究来扩展先前进行的描述性研究，以评估暴露于CYP3A4底物他汀类药物和伴随的3A4抑制剂的患者实际不良事件的相对发生率与非CYP3A4底物他汀类药物和伴随的3A4抑制剂的相对比率。数据来源：健康改善网络。研究设计和方法：一项病例队列研究将用于评估同时暴露于他汀类药物和CYP3A4抑制剂之间的不良事件发生率。不良反应将归因于服用CYP3A4底物他汀组或非CYP3A4底物他汀组。发病率和危险比将使用COX比例风险回归和发病率比使用人-时间泊松回归来确定。影响：拟议研究的结果将提供证据，指导适当选择伴随药物以降低不良事件的风险。此外，这项研究应该阐明他汀类药物氧化代谢差异的影响，特别是关于竞争利用CYP3A4同工酶的影响。临床实践的好处包括为医生提供更多关于他汀类药物与常用药物通过共同代谢途径相互作用的知识。如果结果支持这一假设，医生应该能够识别高风险的药物组合，并潜在地防止严重的药物不良反应。如果不是，则应删除这些警告。这项研究有能力揭示被低估和可预防的药物相互作用的真正潜力。尽管与他汀类药物相关的不良事件不常见，但由于这些药物的广泛使用，此类事件的医疗和经济负担可能是相当大的。尽管他汀类药物和CYP3A4抑制剂之间的药代动力学药物相互作用得到了很好的证明，但现有的数据，包括我们的试点数据(见下文)，表明这种潜在的有害组合要么被忽视，要么被误解。事实上，使这项研究变得重要的是，医生们并没有像认识到这种相互作用一样执业。因此，我们要么停止对此发出警告，要么发出更强烈的警告。

DESCRIPTION (PROVIDED BY APPLICANT): National Cholesterol Education Program (NCEP) guidelines recommend aggressive cholesterol lowering in high risk patients including diabetics and the elderly (> 65 years old). Although statins are very safe drugs, they have the potential for minor and severe adverse reactions, especially when given to patients taking concomitant medications that prolong statin exposure. Specific Aim: To compare the relative incidence of myopathy and acute kidney injury following concomitant use of a CYP3A4 substrate statin [atorvastatin or simvastatin] and a CYP3A4 inhibitor to the incidence of myopathy and acute kidney injury following concomitant use of a non-3A4 substrate statin [fluvastatin, pravastatin, or rosuvastatin] and a CYP3A4 inhibitor. Background and significance: The potentially harmful combination of statins and drugs that inhibit the CYP3A4 isoenzyme are frequently used. This is particularly important since atorvastatin and simvastatin undergo oxidative metabolism by the cytochrome P450 3A4 isoenzyme. The concomitant use of CYP3A4 substrate statins (atorvastatin & simvastatin) and CYP3A4 inhibitors results in increased statin exposure and the potential for increased statin related adverse events. Given the potential for increased statin exposure and related statin adverse events when given concomitantly with a CYP3A4 inhibitor, I propose to expand on previously conducted descriptive studies by conducting a case-cohort study to evaluate the relative rate of actual adverse events for patients exposed to a CYP3A4 substrate statin and a concomitant 3A4 inhibitor (exposed) vs. a non-CYP3A4 substrate statin and a concomitant 3A4 inhibitor. Data source: The Health Improvement Network. Research design and methods: A case-cohort study will be used to evaluate the incidence of adverse events between concomitant exposure to a statin and a CYP3A4 inhibitor. Adverse events will be attributed to either the CYP3A4 substrate statin group or the non-CYP3A4 substrate statin group. Incidence rates and hazard ratios will be determined using Cox proportional hazard regression and incidence rate ratios using person-time Poisson regression. Impact: The results from the proposed study will provide evidence that will guide appropriate selection of concomitant medications to reduce the risk for adverse events. Additionally, the study should elucidate the impact of differential oxidative metabolism of statins, specifically regarding competitive utilization of the CYP3A4 isoenzyme. The benefits to clinical practice include providing physicians with increased knowledge about statin-related drug interactions with frequently used drugs via a common metabolic pathway. If the results support the hypothesis, physicians should be able to identify high-risk drug combinations and potentially prevent serious adverse drug reactions. If not, these warnings should be removed. This study has the capacity to reveal the true potential of an underrated and preventable drug interaction. Although statin-related adverse events are uncommon, the medical and financial burden of such events can be considerable, due to the widespread use of these drugs. Despite the well-documented pharmacokinetic drug interaction between statins and CYP3A4 inhibitors, the available data, including our pilot data (see below), suggest that this potentially harmful combination is either disregarded or misunderstood. Indeed, what makes this study important is that physicians are not practicing as if they recognize this interaction. Thus, either we should stop warning about it, or warn much more emphatically.