Pharmacometric Modeling of Immunosuppressants for Evaluation of Bioequivalence Criteria

项目摘要/摘要 免疫抑制剂包括环孢素、他克莫司、西罗莫司和吗替霉酚酸酯(MMF) 是器官和骨髓移植成功的支柱，被广泛用于预防移植 拒绝。目前还没有关于非专利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导致变量 药物浓度和谷型变异性可能会显著影响患者的治疗。变数很大 药物，如免疫抑制剂，很少达到FDA的生物等效性(BE)标准，因此需要 深入了解药代动力学/药效学(PK/PD)概况，以便评估 成为泛型的标准。在移植患者中的BE研究由于需要大量的样本而受到阻碍 到病人的变异性。移植患者平均同时服用10种不同的药物，包括 多种免疫抑制剂，并存导致药物吸收不良。儿科患者已经被 他克莫司的剂量是成人患者的2-4倍，需要进行儿科专门研究。 应用药物计量建模和模拟技术可以克服对大样本的需要 通过评估PK配置文件和使用部分AUC作为BE标准来确定大小。人口PK/PD建模允许完全 个体PK的广度和深度有待确定，同时保持个体的可变性。的目标是 本项目旨在建立环孢素、他克莫司、西罗莫司和MMF的PK/PD定量模型，以 将品牌名称与仿制药进行比较。这将通过开发特定年龄和药物来实现 特定人群PK模型。临床相关的免疫抑制剂PK/PD模型需要纳入 模型中的标志物将允许预测所需临床效果的实现。目前有 关于这些药物使用部分AUC的现有信息有限。部分AUC是目前的黄金 MMF和环孢素在预测器官排斥反应中的标准，应与他克莫司和 西罗莫司。我们还将在模型中包括一种预测急性排斥反应的PD的新方法 淋巴细胞计数是有效药物治疗与移植物功能测试相结合的标志。包括这些内容 新的PD标记物将扩大确定治疗是否成功的标准。类属词的比较 确保免疫抑制剂在移植患者中的治疗等效性的药物为品牌药物 定义不明确。这项研究的结果将为优化这些资源的使用提供有价值的信息 成人和儿童人群中接受器官移植和骨髓移植的仿制药。 这项研究中开发的方法也将为其他药物类别提供一个更好的平台 在一般评价方面进行评估和利用。

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.