Clinical importance of the drug interaction between statins and SYP3A inhibitors

他汀类药物与 SYP3A 抑制剂之间药物相互作用的临床重要性

• 批准号: 7633266
• 负责人: BRIAN LESLIE STROM
• 金额: $ 5万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7633266
• 关键词: Clinical; importance; drug; interaction; between

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.

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）在内的高风险患者中降低促胆固醇。尽管他汀类药物是非常安全的药物，但它们具有轻微和严重不良反应的潜力，尤其是在服用延长他汀类药物接触的药物的患者时。 具体目的：将肌病和急性肾脏损伤的相对发生率同时使用CYP3A4底物他汀类药物[atorvastatin或simvastatin]和CYP3A4抑制剂与肌病和急性肾脏损伤的发生率与非-3aa4 uspravatin and uspravatin，pravasin and ustratin and substratin， CYP3A4抑制剂。背景和意义：经常使用抑制CYP3A4同工酶的他汀类药物和药物的潜在有害组合。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同工酶经过氧化代谢。 CYP3A4底物他汀类药物（Atorvastatin＆Simvastatin）和CYP3A4抑制剂的伴随使用会导致他汀类药物的暴露增加，并可能增加他汀类药物相关的不良事件。考虑到与CYP3A4抑制剂同时给予他汀类药物暴露和相关的他汀类药物不良事件的可能性增加的可能性，我建议通过进行病例研究研究来扩展先前进行的描述性研究，以评估暴露于CYP3A4蛋白和相关的3Aa4抑制剂（与cypipts nor-Cipts victs）的实际不良事件的相对不良事件的相对发生率3A4抑制剂。数据来源：健康改善网络。研究设计和方法：一项病例研究研究将用于评估与他汀类药物和CYP3A4抑制剂伴随暴露之间不良事件的发生率。不良事件将归因于CYP3A4底物他汀类药物组或非CYP3A4底物他汀类药物组。使用人员时间泊松回归使用COX比例危害回归和发病率比率，将确定发病率和危害比率。影响：拟议研究的结果将提供证据，以指导适当选择伴随药物以降低不良事件的风险。此外，该研究应阐明他汀类药物的差异氧化代谢的影响，特别是关于CYP3A4同工酶的竞争利用。对临床实践的好处包括通过常见的代谢途径为医生提供有关他汀类药物相关药物相互作用的知识。如果结果支持假设，则医生应该能够识别高危药物组合并有可能预防严重的不良药物反应。如果没有，则应删除这些警告。这项研究的能力揭示了被低估和可预防的药物相互作用的真正潜力。尽管与他汀类药物有关的不良事件并不常见，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很大。尽管他汀类药物和CYP3A4抑制剂之间有据可查的药代动力学相互作用，但可用的数据，包括我们的试验数据（请参见下文），这表明这种潜在的有害组合被忽略或误解了。的确，这项研究重要的是医生并没有像他们认识这种相互作用一样练习。因此，要么我们应该停止警告，要么更强调警告。