Age and Race Influences on Immunosuppression after Renal Transplant

年龄和种族对肾移植后免疫抑制的影响

• 批准号: 10208682
• 负责人: KATHLEEN M TORNATORE
• 金额: $ 70.09万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10208682
• 关键词: ABCB1 gene; Address; Adverse drug effect; Adverse effects; African American; Age; Allografting; Area; Attenuated; Biological Models; CD8-Positive T-Lymphocytes; Caucasians; Chronic; Clinical; Clinical Pharmacology; Cost efficiency; Dose; Drug Kinetics; Drug or chemical Tissue Distribution; Elderly; End stage renal failure; Enrollment; Enzymes; Failure; Female; Genomics; Genotype; Graft Rejection; Haplotypes; Hour; Immune response; Immunologics; Immunosuppression; Incidence; Intracellular translocation; Kidney Transplantation; Knowledge; Life Expectancy; Measurement; Membrane; Methods; Modeling; Monitor; Mycophenolic Acid; Organ; Patients; Pharmacodynamics; Pharmacogenomics; Pharmacology; Pharmacology Study; Race; Regimen; Regulatory T-Lymphocyte; Renal Replacement Therapy; Renal function; Research; Research Design; Risk; Sex Differences; Standardization; Statistical Models; Tacrolimus; Transmembrane Transport; Transplant Recipients; United States; Variant; absorption; age difference; age effect; allograft rejection; base; clinical phenotype; comorbidity; design; drug metabolism; evidence base; experience; genetic variant; improved; innovation; male; middle age; novel; nuclear factors of activated T-cells; older patient; personalized medicine; pharmacodynamic model; pharmacokinetics and pharmacodynamics; prevent; racial difference; response; sex

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.

抽象的 在美国，终阶段肾脏疾病的事件继续增加。年龄调整后的率 在非洲裔美国人中，末期肾脏疾病比高加索人高4倍 老年患者。肾移植是由于成本效率和 不论年龄，种族或性别如何，都会改善预期寿命。肾移植在接受者中增加了一倍以上 ≥65岁的非裔美国人继续增加。他克莫司和霉酚酸是最大的 规定的常见方案以减弱免疫反应并避免同种异体移植排斥。老年肾脏 移植接收者可能会收到较旧的功能性器官。增加年龄是慢性的独立风险 同种异体移植失败表明需要对年龄调整的给药方案。另外，慢性全链移植存活率为 非洲裔美国人比白种人差，这可能是由于免疫抑制的种族差异 药代动力学，基因组因素，合并症和免疫反应。临床药理学研究 在年龄的领域，免疫抑制药代动力学和药效学的种族和性别差异是 缺乏导致主要知识差距，阻碍了证据的个性化 免疫抑制剂。该建议将解决此知识差距，并确定年龄，种族的影响 以及对他克莫司和霉酚酸的药代动力学和药效学的性别。这项研究将注册 216稳定的非裔美国人和高加索男性和女性肾移植接受者将分层 进入年轻，中年和年龄段。我们假设那个年龄，种族和性别独立，并且 可能的联合影响，对免疫抑制药物动力学和药效反应以及 这种作用是在某些影响药物代谢和膜的某些基因型的患者中的潜在作用 运输。具体目的是：1）研究年龄，种族和性别对药代动力学的影响 他克莫司和霉酚酸以及与药物相关的药物基因组变体的影响 代谢和组织分布。 2）调查年龄，种族和性别的关联 药物动态反应，包括不良药物作用，调节细胞，细胞P-gp功能， 细胞内NFAT1易位及其与免疫抑制药代动力学的关系。 3）利用 基于机制的药代动力学和药效系统模型，以确定年龄的关系， 使用T调节细胞P-gp的种族和性别对他克莫司和MPA药代动力学和药效学 功能和NFAT1易位，不良反应，肾功能和基因变体。这些目标将促进 通过提供非特异性临床监测方法的桥梁，免疫抑制的重大进展 目前使用并创建新颖的剂量和监测方法，将年龄，种族和性别与蜂窝融为一体 以及临床终点，药代动力学和药物基因组学以获得个性化医学。