Pharmacometric Modeling of Immunosuppressants for Evaluation of Bioequivalence Criteria

用于评估生物等效性标准的免疫抑制剂药理学模型

• 批准号: 8853626
• 负责人: Catherine Mary Turner Sherwin
• 金额: $ 25万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-10 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8853626
• 关键词: Pharmacometric; Modeling; Immunosuppressants; Evaluation; Bioequivalence

PROJECT SUMMARY/ABSTRACT Immunosuppressant agents including cyclosporine, tacrolimus, sirolimus, and mofetil mycophenolate (MMF) are the backbone of organ and bone marrow transplant success and are widely used to prevent transplant rejection. There have not been definitive reports of clinical failures with generic immunosuppressants. However, generic substitution for brand name immunosuppressants has been shown to result in variable concentrations and to have trough variability that may significantly impact the patient's therapy. Highly variable drugs, such as immunosuppressants, seldom meet FDA bioequivalence (BE) criteria and therefore require in depth understanding of the pharmacokinetic/pharmacodynamic (PK/PD) profile to allow assessment against BE criteria for generics. BE studies in transplant patients are hampered by the need for large sample sizes due to patient variability. Transplant patients take on average ten different medications simultaneously, including multiple immunosuppressants, and absorb drugs poorly due to comorbidities. Pediatric patients have been shown to require 2-4 times the dose of tacrolimus than adult patients necessitating pediatric specific studies. Application of pharmacometric modeling and simulation techniques can overcome the need for a large sample size by evaluating PK profiles and using partial AUCs as BE criteria. Population PK/PD modeling allows the full breadth and depth of the individual PK to be determined, while preserving individual variability. The objective of this project is to develop quantitative PK/PD models for cyclosporine, tacrolimus, sirolimus, and MMF to compare brand name to the generic formulations. This will be done by developing age-specific and drug specific population PK models. Clinically relevant PK/PD models for immunosuppressants require the inclusion of markers in the model that will allow prediction of achievement of desired clinical effect. There is currently limited information available on the use of partial AUCs for these drugs. Partial AUCs are currently the gold standard for MMF and cyclosporine in predicting organ rejection, and should be comparable for tacrolimus and sirolimus. We will also include in the model a novel approach to PD for predicting acute rejection using lymphocyte counts as a marker for effective drug therapy paired with graft function tests. Inclusion of these novel PD makers will expand the criteria for determining if therapy is successful. The comparison of generic drugs to brand names drugs to assure therapeutic equivalence in immunosuppressants in transplant patients is not well defined. The outcomes from this study will provide valuable information to optimize the use of these generic drugs within adult and pediatric populations receiving organ transplants and bone marrow transplants. The methods developed in this study will also provide a platform from which other drug classes could be better assessed and utilized with respect to generic evaluation.

项目概要/摘要 免疫抑制剂，包括环孢素、他克莫司、西罗莫司和吗替麦考酚酯 (MMF) 是器官和骨髓移植成功的支柱，并广泛用于预防移植 拒绝。目前还没有关于仿制药免疫抑制剂临床失败的明确报告。 然而，品牌免疫抑制剂的仿制药替代已被证明会导致不同的结果 浓度并具有可能显着影响患者治疗的低谷变异性。高度可变 免疫抑制剂等药物很少符合 FDA 生物等效性 (BE) 标准，因此需要 深入了解药代动力学/药效学 (PK/PD) 概况，以便进行评估 仿制药的 BE 标准。由于需要大样本量，移植患者的 BE 研究受到阻碍 患者的变异性。移植患者平均同时服用十种不同的药物，包括 多种免疫抑制剂，并且由于合并症而吸收药物不良。儿科患者已 需要进行儿科专门研究，表明需要比成人患者多 2-4 倍的他克莫司剂量。 药理学建模和模拟技术的应用可以克服对大样本的需求 通过评估 PK 概况并使用部分 AUC 作为 BE 标准来确定大小。群体 PK/PD 建模允许充分 个体 PK 的广度和深度待确定，同时保持个体差异。的目标 该项目旨在开发环孢素、他克莫司、西罗莫司和 MMF 的定量 PK/PD 模型，以 将品牌名称与通用配方进行比较。这将通过开发针对年龄的药物来完成 特定人群PK模型。免疫抑制剂的临床相关 PK/PD 模型需要纳入 模型中的标记物将允许预测所需临床效果的实现。目前有 关于使用这些药物的部分 AUC 的可用信息有限。部分 AUC 目前是黄金 MMF 和环孢菌素在预测器官排斥方面的标准，并且他克莫司和环孢菌素应该具有可比性 西罗莫司。我们还将在模型中包含一种新的 PD 方法，用于预测急性排斥反应 淋巴细胞计数可作为有效药物治疗与移植物功能测试相结合的标志物。包含这些 新型 PD 制造商将扩大确定治疗是否成功的标准。通用型的比较 药物与品牌药物的比较，以确保免疫抑制剂对移植患者的治疗等效性 没有明确定义。这项研究的结果将为优化这些技术的使用提供有价值的信息 接受器官移植和骨髓移植的成人和儿童人群中的仿制药。 本研究开发的方法还将提供一个平台，其他药物类别可以在此平台上取得更好的效果 就一般评价进行评估和利用。