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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.

项目总结/摘要免疫检查点抑制剂已显示出显著的肿瘤学功效，但其临床益处受到以下因素的限制：治疗限制性不良事件。检查点抑制剂的功效来自于T细胞活化，引发促炎细胞因子的产生增加。已知促炎细胞因子抑制肝脏药物代谢酶，包括细胞色素P450（CYP）家族成员，增加与联合给药的底物的暴露和潜在不良事件。既然检查- 点抑制剂被配制成不直接与酶或药物相互作用的单克隆抗体转运蛋白，开发期间未进行临床药物相互作用研究。然而，PO- 与检查点抑制剂的临床相关药物相互作用的可能性得到了以下研究的支持，发现在与底物共同给药期间不良事件增加，包括特殊不良事件，对共同给药的底物有特异性。这些发现表明，检查点治疗期间的不良事件- TOR治疗可能部分由药物相互作用引起，药物相互作用增加了不良事件的可能性，联合用药。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， GIES以减少检查点抑制剂治疗期间的不良事件，从而增强其临床益处。本研究的长期目标是确定临床策略，以管理检查期间的不良事件。穴位抑制疗法该建议的研究目的是（1）确定检查点的影响， TOR治疗对受体探针药物代谢和受体底物药物不良事件风险的影响和（2）确定促炎细胞因子之间的关联在检查点抑制剂治疗之前和期间的药物浓度和药物代谢。探讨为了实现这些目标，我们将进行一项两阶段交叉临床药物相互作用研究，给予6种CYP酶（CYP 1A 2、CYP 2B 6、CYP 2C 9、CYP 2C 19、CYP 2D 6和CYP 3A）的探针药物，在受试者开始检查点抑制剂治疗之前和之后对他们进行测试。将计算代谢率从探针药物及其代谢物的浓度来评估药物代谢的潜在变化。代谢率的变化将被纳入基于生理学的药代动力学模型，估计暴露和不良事件变化的可能性，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）。将在两个研究阶段测定促炎细胞因子浓度，以确定其潜在作用。与代谢率的相关性。该提案的预期成果是建立一个对检查点通道介导的药物相互作用的机制理解，将（1）告知临床管理这些交互的策略（例如，治疗性替代代谢途径未受影响的药物- 方法）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.