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）指南建议高风险患者（包括糖尿病患者和老年人（> 65岁））积极降低胆固醇。虽然他汀类药物是非常安全的药物，但它们有可能发生轻微和严重的不良反应，特别是当患者服用延长他汀类药物暴露的合并药物时。 具体目标：比较伴随使用CYP 3A 4底物他汀类药物[阿托伐他汀或辛伐他汀]和CYP 3A 4抑制剂后肌病和急性肾损伤的相对发生率与伴随使用非3A 4底物他汀类药物[氟伐他汀、普伐他汀或瑞舒伐他汀]和CYP 3A 4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CYP 3A 4同工酶的药物的潜在有害组合经常使用。这是特别重要的，因为阿托伐他汀和辛伐他汀通过细胞色素P450 3A 4同工酶进行氧化代谢。同时使用CYP 3A 4底物他汀类药物（阿托伐他汀和辛伐他汀）和CYP 3A 4抑制剂导致他汀类药物暴露增加，并可能增加他汀类药物相关不良事件。考虑到与CYP 3A 4抑制剂同时给药时他汀类药物暴露增加和相关他汀类药物不良事件的可能性，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，以评价暴露于CYP 3A 4底物他汀类药物和伴随3A 4抑制剂（暴露）与非3A 4抑制剂的患者的实际不良事件的相对发生率。CYP 3A 4底物他汀类药物和伴随的3A 4抑制剂。数据来源：健康改善网络。研究设计和方法：将使用病例队列研究评价他汀类药物和CYP 3A 4抑制剂合并暴露之间不良事件的发生率。不良事件将归因于CYP 3A 4底物他汀类药物组或非CYP 3A 4底物他汀类药物组。使用考克斯比例风险回归确定发生率和风险比，使用人-时间泊松回归确定发生率比。影响：拟议研究的结果将提供证据，指导适当选择合并用药，以降低不良事件的风险。此外，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CYP 3A 4同工酶的竞争性利用。临床实践的益处包括为医生提供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更多知识。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，并可能防止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。虽然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CYP 3A 4抑制剂之间的药代动力学药物相互作用有充分的记录，但现有数据，包括我们的初步数据（见下文），表明这种潜在有害的组合被忽视或误解。事实上，这项研究之所以重要，是因为医生们并没有认识到这种相互作用。因此，我们要么停止警告，要么更强烈地警告。