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：
10677895
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/10677895
关键词：
Adverse event Affect 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 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 Therapeutic Toxic effect Tramadol Translational Research Tyrosine Kinase Inhibitor adverse event risk cancer therapy career checkpoint therapy clinical development clinical practice clinical risk clinically relevant comorbidity cytokine drug metabolism high risk immune-related adverse events member models and simulation novel therapeutics pharmacokinetic model post-market 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.

项目摘要/摘要免疫检查点抑制剂已显示出显着的肿瘤功效，但其临床益处受到限制治疗限制不良事件。检查点抑制剂的功效引起的T细胞激活，这也是触发促炎细胞因子的产生增加。促炎性细胞因子已知会抑制肝药物代谢酶，包括细胞色素P450（CYP）家族的成员，从而增加了与共同管理CYP底物的不良事件的暴露和潜力。由于检查 - 点抑制剂被配制为不直接与CYP酶或药物相互作用的单克隆抗体转运蛋白，在发育过程中未进行临床药物相互作用研究。但是，临床相关的药物与检查点抑制剂相关的药物相互作用的结果由已有的研究支持发现与CYP底物共同给药期间的不良事件增加了，包括不良事件 cific至共同管理的CYP底物。这些发现表明检查点抑制期间的不良事件 TOR治疗可能部分是由药物相互作用引起的，这些相互作用增加了与共同管理药物。这些新型药物相互作用的发现可能会为临床策略提供信息在检查点抑制剂疗法期间减少不良事件的GIE，从而提高其临床益处。这项研究的长期目标是确定在检查期间管理不良事件的临床策略 - 点抑制剂疗法。该提案的研究目的是（1）确定检查点抑制的影响 TOR治疗CYP探测药物的代谢以及CYP底物药物不良事件的风险通常向癌症患者开处方，（2）确定促炎性细胞因子之间的关联在检查点抑制剂治疗之前和期间，浓度和CYP探测药物代谢。调查这些目的，我们将进行两阶段的跨界临床药物相互作用研究，其中含有鸡尾酒用于六种CYP酶（CYP1A2，CYP2B6，CYP2C9，CYP2C19，CYP2D6和CYP3A）的探针药物。启动检查点抑制剂治疗前后受试者。将计算代谢比率从探针药物及其代谢产物的浓度来评估CYP代谢的潜在变化。 CYP代谢比的变化将纳入基于生理的药代动力学模型与估计使用CYP底物药物的暴露和不良事件变化的可能性 Monly向具有严重不良事件的癌症患者开了处方（例如Citalopram，Tramadol，芬太尼）。促炎性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TIAL关联。该提议的预期结果是建立对检查点抑制剂介导的药物相互作用的机械理解，该相互作用将为临床管理这些相互作用的策略（例如，用未影响代谢路径的药物替代治疗性替代方式）和（2）阐明细胞因子特征，以识别这些药物相互作用风险最高的患者。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Patient understanding of pharmacogenomic test results in clinical care.

临床护理中患者对药物基因组学测试结果的了解。

DOI：
10.1016/j.pec.2023.107904
发表时间：
2023
期刊：
Patient education and counseling
影响因子：
3.5
作者：
Doyle,TomA;Schmidt,KarenK;Halverson,ColinME;Olivera,Jesus;Garcia,Abigail;Shugg,TylerA;Skaar,ToddC;Schwartz,PeterH
通讯作者：
Schwartz,PeterH

Computational pharmacogenotype extraction from clinical next-generation sequencing.

DOI：
10.3389/fonc.2023.1199741
发表时间：
2023
期刊：
FRONTIERS IN ONCOLOGY
影响因子：
4.7
作者：
Shugg, Tyler;Ly, Reynold C.;Osei, Wilberforce;Rowe, Elizabeth J.;Granfield, Caitlin A.;Lynnes, Ty C.;Medeiros, Elizabeth B.;Hodge, Jennelle C.;Breman, Amy M.;Schneider, Bryan P.;Sahinalp, S. Cenk;Numanagic, Ibrahim;Salisbury, Benjamin A.;Bray, Steven M.;Ratcliff, Ryan;Skaar, Todd C.
通讯作者：
Skaar, Todd C.

Association of QT interval-prolonging drugs with clinical trial eligibility in patients with advanced cancer.

DOI：
10.3389/fcvm.2022.894623
发表时间：
2022
期刊：
FRONTIERS IN CARDIOVASCULAR MEDICINE
影响因子：
3.6
作者：
Rowe, Elizabeth J.;Shugg, Tyler;Ly, Reynold C.;Philips, Santosh;Rosenman, Marc B.;Callaghan, John T.;Radovich, Milan;Overholser, Brian R.;Schneider, Bryan P.;Tisdale, James E.;Skaar, Todd C.
通讯作者：
Skaar, Todd C.