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.

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岁以上）在内的高风险患者中积极降低胆固醇。虽然他汀类药物是非常安全的药物，但它们有可能产生轻微和严重的不良反应，特别是当患者同时服用延长他汀类药物暴露的药物时。特定目的：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抑制剂与同时使用非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相对发生率。背景与意义：他汀类药物与抑制CYP3A4同工酶的药物经常联合使用。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抑制剂导致他汀类药物暴露增加和他汀类药物相关不良事件增加的可能性。考虑到他汀类药物与CYP3A4抑制剂联合使用可能会增加他汀类药物的暴露量和相关的他汀类药物不良事件，我建议通过开展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底物他汀类药物和同时使用3A4抑制剂（暴露）与非CYP3A4底物他汀类药物和同时使用3A4抑制剂的患者实际不良事件的相对发生率。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抑制剂之间不良事件的发生率。不良事件将归因于CYP3A4底物他汀组或非CYP3A4底物他汀组。发病率和风险比采用Cox比例风险回归确定，发病率比采用人-时间泊松回归确定。影响：拟议研究的结果将提供证据，指导适当选择伴随药物，以减少不良事件的风险。此外，该研究应阐明他汀类药物差异氧化代谢的影响，特别是关于CYP3A4同工酶的竞争性利用。对临床实践的好处包括为医生提供有关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。如果结果支持假设，医生应该能够识别高风险药物组合并潜在地预防严重的药物不良反应。如果没有，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相当大。尽管他汀类药物和CYP3A4抑制剂之间的药代动力学相互作用有充分的文献记载，但现有的数据，包括我们的试点数据（见下文）表明，这种潜在有害的组合要么被忽视，要么被误解。事实上，这项研究的重要之处在于，医生们并没有意识到这种相互作用。因此，我们要么停止警告，要么更加强调警告。