Investigation of the Immune-Mediated Drug-Drug Interaction Potential of Immune Checkpoint Inhibitors

免疫检查点抑制剂免疫介导的药物相互作用潜力的研究

基本信息

批准号：
10506483
负责人：
Tyler A Shugg
金额：
$ 16.73万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10506483
关键词：
Adverse event Affect Ally Biological Assay CYP1A2 gene CYP2B6 gene CYP2C19 gene CYP2C9 gene CYP2D6 gene CYP3A4 gene Cancer Patient Citalopram Clinical Clinical Management Clinical Research Clinical Trials Collaborations Cytochrome P450 Data Development Drug Interactions Enzymes Family Fentanyl Funding Future Goals Hepatic Immune Immune checkpoint inhibitor Inflammatory Interleukin-6 Investigation Knowledge Lead Malignant Neoplasms Marketing Measures Mediating Mentored Patient-Oriented Research Career Development Award Mentors Metabolic Metabolic Pathway Metabolism Methodology Methods Monoclonal Antibodies Opioid Analgesics Outcome Patients Pharmaceutical Preparations Phase Physiological Positioning Attribute Production Public Health Regulation Research Research Technics Risk Safety Serious Adverse Event Study models Supportive care T-Cell Activation T-Lymphocyte Therapeutic Toxic effect Tramadol Translational Research Tweens Tyrosine Kinase Inhibitor adverse event risk base cancer therapy career checkpoint therapy clinical development clinical practice clinical risk clinically relevant comorbidity cytokine drug metabolism high risk immune-related adverse events inhibitor member models and simulation novel therapeutics pharmacokinetic model prevent programs prospective stem translational approach translational goal

项目摘要

PROJECT SUMMARY/ABSTRACT Immune checkpoint inhibitors have shown remarkable oncologic efficacy, but their clinical benefit is limited by treatment-limiting adverse events. The efficacy of checkpoint inhibitors results from T-cell activation, which also triggers increased production of pro-inflammatory cytokines. Pro-inflammatory cytokines are known to inhibit hepatic drug-metabolizing enzymes, including members of the cytochrome P450 (CYP) family, and thereby increase the exposure and potential for adverse events with co-administered CYP substrates. Since check- point inhibitors are formulated as monoclonal antibodies that do not directly interact with CYP enzymes or drug transporters, clinical drug-drug interaction studies were not performed during development. However, the po- tential for clinically relevant drug-drug interactions with checkpoint inhibitors is supported by studies that have found increased adverse events during co-administration with CYP substrates, including adverse events spe- cific to co-administered CYP substrates. These findings suggest that adverse events during checkpoint inhibi- tor therapy may be, in part, caused by drug-drug interactions that increase the potential for adverse events with co-administered medications. Discovery of these novel drug-drug interactions will likely inform clinical strate- gies to reduce adverse events during checkpoint inhibitor therapy and thereby enhance their clinical benefit. The long-term goal of this research is to identify clinical strategies to manage adverse events during check- point inhibitor therapy. The research aims of this proposal are (1) to determine the impact of checkpoint inhibi- tor therapy on the metabolism of CYP probe drugs and the risk for adverse events with CYP substrate drugs commonly prescribed to cancer patients and (2) to identify associations between pro-inflammatory cytokine concentrations and CYP probe drug metabolism before and during checkpoint inhibitor therapy. To investigate these aims, we will conduct a two-phase crossover clinical drug interaction study in which a cocktail containing probe drugs for six CYP enzymes (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A) is adminis- tered to subjects before and after they initiate checkpoint inhibitor therapy. Metabolic ratios will be calculated from concentrations of probe drugs and their metabolites to assess potential changes in CYP metabolism. Changes in CYP metabolic ratios will be incorporated into physiologically-based pharmacokinetic models to estimate the potential for changes in exposure and adverse events with CYP substrate drugs that are com- monly prescribed to cancer patients with the potential for serious adverse events (e.g., citalopram, tramadol, fentanyl). Pro-inflammatory cytokine concentrations will be assayed in both study phases to determine poten- tial associations with CYP probe metabolic ratios. The expected outcomes of this proposal are to establish a mechanistic understanding of checkpoint inhibitor-mediated drug-drug interactions that will (1) inform clinical strategies to manage these interactions (e.g., therapeutic substitution to drugs with unaffected metabolic path- ways) and (2) elucidate cytokine signatures to identify patients at highest risk for these drug interactions.

项目概要/摘要免疫检查点抑制剂已显示出显着的肿瘤疗效，但其临床益处受到以下因素的限制：限制治疗的不良事件。检查点抑制剂的功效来自于 T 细胞激活，这也触发促炎细胞因子的产生增加。已知促炎细胞因子可抑制肝脏药物代谢酶，包括细胞色素 P450 (CYP) 家族的成员，从而与共同施用的 CYP 底物增加不良事件的暴露和可能性。自从检查以来—— 点抑制剂被配制为单克隆抗体，不直接与 CYP 酶或药物相互作用转运蛋白，在开发过程中未进行临床药物相互作用研究。然而，临床相关的药物与检查点抑制剂之间的相互作用的可能性得到了以下研究的支持发现与 CYP 底物共同给药期间不良事件增加，包括特定的不良事件与共同施用的 CYP 底物有关。这些发现表明，检查点抑制期间的不良事件治疗可能部分是由药物之间的相互作用引起的，这种相互作用增加了不良事件的可能性共同服用的药物。这些新的药物相互作用的发现可能会为临床策略提供信息旨在减少检查点抑制剂治疗期间的不良事件，从而增强其临床效益。这项研究的长期目标是确定在检查过程中管理不良事件的临床策略点抑制剂治疗。该提案的研究目的是（1）确定检查点抑制的影响治疗对 CYP 探针药物代谢以及 CYP 底物药物不良事件风险的影响通常用于癌症患者；(2) 确定促炎细胞因子之间的关联检查点抑制剂治疗之前和期间的浓度和 CYP 探针药物代谢。调查为了实现这些目标，我们将进行两阶段交叉临床药物相互作用研究，其中含有六种 CYP 酶（CYP1A2、CYP2B6、CYP2C9、CYP2C19、CYP2D6 和 CYP3A）的探针药物被施用在受试者开始检查点抑制剂治疗之前和之后进行研究。将计算代谢比率从探针药物及其代谢物的浓度来评估 CYP 代谢的潜在变化。 CYP 代谢比率的变化将被纳入基于生理学的药代动力学模型中，以估计 CYP 底物药物的暴露变化和不良事件的可能性仅开给可能发生严重不良事件的癌症患者（例如西酞普兰、曲马多、芬太尼）。促炎细胞因子浓度将在两个研究阶段进行测定，以确定潜在的与 CYP 探针代谢比率的重要关联。该提案的预期成果是建立一个对检查点抑制剂介导的药物相互作用的机制理解将（1）为临床提供信息管理这些相互作用的策略（例如，用不受影响的代谢途径的药物进行治疗替代）方式）和（2）阐明细胞因子特征，以确定这些药物相互作用风险最高的患者。