Pharmacometric Modeling of Immunosuppressants for Evaluation of Bioequivalence Criteria

项目总结/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，并广泛用于防止移植 排斥反应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，已证明用非专利药替代品牌免疫抑制剂会导致可变的 浓度和谷值变异性可能会显著影响患者的治疗。高度可变 药物，如免疫抑制剂，很少符合FDA生物等效性（BE）标准，因此需要在 深入了解药代动力学/药效学（PK/PD）特征，以便评估 仿制药的BE标准。移植患者的BE研究受到需要大样本量的阻碍， 患者的变异性。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，并且由于合并症而吸收药物差。儿科患者一直 显示需要比成人患者2-4倍剂量的他克莫司，需要儿科特定研究。 应用药物计量学建模和模拟技术可以克服对大样本的需要 通过评价PK特征并使用部分AUC作为BE标准来确定剂量。群体PK/PD建模允许完整的 确定个体PK的广度和深度，同时保留个体变异性。的目标 本项目旨在开发环孢素、他克莫司、西罗莫司和霉酚酸酯的定量PK/PD模型， 将品牌名称与通用配方进行比较。这将通过开发特定年龄和药物 特定群体PK模型。免疫抑制剂的临床相关PK/PD模型需要纳入 模型中的标志物将允许预测达到期望的临床效果。目前 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 霉酚酸酯和环孢霉素在预测器官排斥反应方面的标准，与他克莫司和 西罗莫司。我们还将在模型中包括一种新的PD方法，用于预测急性排斥反应， 淋巴细胞计数作为有效药物治疗的标志物，并与移植物功能试验配对。包含这些 新的PD标记物将扩大确定治疗是否成功的标准。通用的比较 确保移植患者中免疫抑制剂的治疗等效性的品牌药物， 没有很好的定义。这项研究的结果将提供有价值的信息，以优化这些 接受器官移植和骨髓移植的成人和儿童人群中的仿制药。 本研究中开发的方法也将提供一个平台，使其他药物类别可以更好地 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.