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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Model-Based Assessment Using Conventional Bioequivalence Limits to Ensure Safety and Efficacy of Rivaroxaban in Patients Undergoing Hip or Knee Replacement
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Model-Based Assessment Using Conventional Bioequivalence Limits to Ensure Safety and Efficacy of Rivaroxaban in Patients Undergoing Hip or Knee Replacement

机译：基于模型的基于模型评估，使用常规生物等效性限制，以确保Rivaroxaban在接受髋关节或膝关节置换的患者中的安全性和有效性

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We evaluated whether the current bioequivalence limit is adequate to ensure safety and efficacy of rivaroxabanin patients undertotal hip arthroplasty and total knee arthroplastybased on its model informed benefit/risk profile. Clinical data from a total of 7145 patients from 3 phase 2 and 4 phase 3 clinical trials were included in the current model-based exposure-response analysis. The relationships between rivaroxaban exposure measurements (ie,minimum or trough, maximum, average concentration, and area under the concentration-time curve [AUC] at steady state)and clinical outcomes (ie, the probabilities of major bleeding [MB] andvenous thromboembolism [VTE]) were modeled using NONMEM7.3.Model evaluation was performed using predictive checks and nonparametric bootstrap. Simulations were conducted to assess the study objectives.A shallow relationship was observed between explored exposure measurements within the tested dose range and the probability of VTE following rivaroxaban treatment.Trough concentrations were found to be a statistically significant predictor of the probability of MB. This relationship was better described using a power function. Model validation confirmed model adequacy. Based on the simulations results, the relative risk of MB of a hypothetical test product (with 20% change in AUC) will not statistically differ from the brand name drug.Twenty percentAUC variations do not change the relative risk of MB and is unlikely to compromise efficacy of therapy. A generic drug of rivaroxaban passing the typical bioequivalence assessment is expected to have similar safety and efficacy as the brand name drug.
机译：我们评估了目前的生物等效限制是否足以确保罗马昔巴宁患者的安全性和疗效患者髋关节关节置换术和全膝关节换向术上其模型知情福利/风险概况。来自3阶段2和4阶段3临床试验的总共7145名患者的临床资料包括在目前的基于模型的曝光响应分析中。 rivaroxaban曝光测量（即，稳态浓度 - 时间曲线[AUC]下的最小或槽，最大，平均浓度和面积的关系）和临床结果（即，主要出血的概率[MB] andphone血栓栓塞[ VTE]）使用NONMEM7.3模型建模..使用预测检查和非参数举止进行评估。进行了仿真以评估研究目标。在测试剂量范围内探讨的曝光测量和亚甲氧基亚甲烷处理后VTE的概率观察到浅的关系。发现浓度是MB概率的统计上显着的预测因子。使用功率函数更好地描述这种关系。模型验证确认模型充足性。基于模拟结果，假设的测试产品的MB的相对风险（AUC的20％）与品牌药物没有统计不同.TWenty Perceauc的变化不会改变MB的相对风险，不太可能妥协治疗疗效。通过典型的生物等效性评估的rivaroxaban的仿制药预计将具有与品牌药物相似的安全性和疗效。

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