Age and Race Influences on Immunosuppression after Renal Transplant

摘要 在美国，终末期肾病的发病率持续增加。年龄调整率 非裔美国人中终末期肾病的发生率是白人的4倍， 老年患者。肾移植是首选的肾脏替代疗法，由于成本效益和 提高预期寿命，不分年龄、种族或性别。接受肾移植的人增加了一倍多 ≥ 65岁，非洲裔美国人持续增加。他克莫司和霉酚酸是最 常用的治疗方案是减弱免疫反应和避免同种异体移植排斥反应。老年肾脏病 移植受者可能会接受年龄较大、功能较差的器官。年龄增长是慢性病的独立风险 同种异体移植失败，提示需要年龄调整的给药方案。此外，慢性同种异体移植物存活率 非洲裔美国人比高加索人更穷，这可能是由于免疫抑制剂的种族差异。 药代动力学、基因组因素、共病和免疫应答。临床药理研究 免疫抑制药代动力学和药效学的年龄、种族和性别差异 缺乏导致重大的知识差距，阻碍以证据为基础的，个性化的 免疫抑制剂。这项提案将解决这一知识差距，并确定年龄，种族， 性别对他克莫司和霉酚酸药代动力学和药效学的影响。本研究将招募 216例稳定的非裔美国人和高加索男性和女性肾移植受者将被分层 分为年轻人、中年人和老年人。我们假设年龄、种族和性别是独立的， 对免疫抑制药代动力学和药效学反应的可能联合影响， 这种效应在具有影响药物代谢和膜的某些基因型的患者中增强， 运输具体目的是：1）研究年龄、种族和性别对药物动力学的影响。 他克莫司和霉酚酸以及与药物相关的药物基因组学变异体的影响 代谢和组织分布。2)目的探讨年龄、种族、性别与住院病人死亡的关系。 药效学反应，包括药物不良反应、T调节细胞、细胞P-gp功能， 细胞内NFAT 1易位及其与免疫抑制药代动力学关系。3)利用 基于机制的药代动力学和药效学系统模型，以确定年龄， 人种和性别对他克莫司和MPA药代动力学和药效学的影响，使用T调节细胞，P-gp 功能和NFAT 1易位，不良反应，肾功能和基因变异。这些目标将促进 免疫抑制的重大进展，提供了一个桥梁，从非特异性的临床监测方法 目前使用的，并创造新的剂量和监测方法，整合年龄，种族和性别与细胞 以及临床终点、药代动力学和药物基因组学，以实现个性化用药。

ABSTRACT The incidence of end stage renal disease in the United States has continued to increase. The age-adjusted rate of end stage renal disease is 4x greater in African Americans than Caucasians with an increased incidence in elderly patients. Renal transplantation is the preferred renal replacement therapy due to cost efficiency and improved life expectancy, regardless of age, race or sex. Renal transplant has more than doubled in recipients ≥ 65 years with a continued increase in African Americans. Tacrolimus and mycophenolic acid is the most common regimen prescribed to attenuate immunologic responses and avoid allograft rejection. Elderly renal transplant recipients may receive older, less functional organs. Increased age is an independent risk for chronic allograft failure suggesting the need for age-adjusted dosing regimens. In addition, chronic allograft survival is poorer in African Americans than Caucasians, which may be due to racial differences in immunosuppressive pharmacokinetics, genomic factors, co-morbidities and immunologic responses. Clinical pharmacology research in the area of age, race and sex differences in immunosuppressive pharmacokinetics and pharmacodynamics is lacking leading to a major knowledge gap that impedes evidence-based, individualization of immunosuppressives. This proposal will address this knowledge gap and determine the influence of age, race and sex on pharmacokinetics and pharmacodynamics of tacrolimus and mycophenolic acid. This study will enroll 216 stable African American and Caucasian male and female renal transplant recipients that will be stratified into young, middle age and elderly groups. We hypothesize that age, race and sex exert independent, and possible combined influences, on immunosuppressive pharmacokinetics and pharmacodynamic responses and this effect is potentiated in patients with certain genotypes that influence drug metabolism and membrane transport. The Specific Aims are: 1) To investigate the effect of age, race, and sex on the pharmacokinetics of tacrolimus and mycophenolic acid and the influence of pharmacogenomic variants associated with drug metabolism and tissue distribution. 2) To investigate the association of age, race and sex on intrapatient pharmacodynamic responses including adverse drug effects, T regulatory cells, cellular P-gp function, intracellular NFAT1 translocation and their relationship to immunosuppressive pharmacokinetics. 3) Utilize mechanism-based pharmacokinetic and pharmacodynamic system models to determine the relationship of age, race and sex to tacrolimus and MPA pharmacokinetics and pharmacodynamics using T regulatory cells, P-gp function, and NFAT1 translocation, adverse effects, renal function and gene variants. These aims will promote major progress in immunosuppression by providing a bridge from the non-specific clinical monitoring methods currently used and create novel dosing and monitoring approaches that integrate age, race and sex with cellular and clinical endpoints, pharmacokinetics and pharmacogenomics to attain personalized medicine.