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

• 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
• 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

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著的肿瘤学疗效，但其临床益处受到以下因素的限制 治疗--限制不良事件。检查点抑制剂的疗效来自T细胞的激活，这也是 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 增加联合使用CYP底物的暴露和不良事件的可能性。因为检查了- 点抑制剂是以不直接与CYP酶或药物相互作用的单抗形式配制的 在开发过程中没有进行转运蛋白、临床药物-药物相互作用研究。然而，PO- 临床相关药物与检查点抑制剂相互作用的可能性得到了以下研究的支持 发现在与CYP底物联合给药期间不良事件增加，包括不良事件特别是 CICC到联合给药的CYP底物。这些发现表明，检查点期间的不良事件会抑制- TOR治疗的部分原因可能是药物-药物相互作用增加了发生不良事件的可能性 联合用药。这些新的药物-药物相互作用的发现可能会为临床策略提供信息。 GES可减少检查点抑制剂治疗期间的不良事件，从而提高其临床效益。 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- 穴位抑制疗法。这项建议的研究目的是：(1)确定检查站管制的影响。 TOR疗法对环磷酰胺探针药物代谢及与环磷酰胺底物药物不良事件风险的影响 通常开给癌症患者和(2)确定促炎细胞因子之间的联系 检查点抑制剂治疗前和治疗期间的血药浓度和CYP检测药物代谢。去调查 为了达到这些目标，我们将进行一项两阶段交叉临床药物相互作用研究，在该研究中，一种含有 六种细胞色素P450酶(CYP1A2、CYP2B6、CYP2C9、CYP2C19、CYP2D6和CYP3A)的探针药物是用药。 在开始检查点抑制剂治疗前后对受试者进行测试。将计算代谢率 从探针药物及其代谢物的浓度来评估CYP代谢的潜在变化。 CYP代谢率的变化将被纳入基于生理的药代动力学模型中 评估使用CYP底物药物的暴露和不良事件发生变化的可能性。 单处方给可能发生严重不良事件的癌症患者(如西酞普兰、曲马多、 芬太尼)。将在两个研究阶段检测促炎细胞因子浓度，以确定潜在的- TIAL与CYP探针代谢率的关系。这项提议的预期结果是建立一个 检查点抑制剂介导的药物-药物相互作用的机制理解将(1)告知临床 管理这些相互作用的策略(例如，对代谢途径不受影响的药物的治疗性替代- 方法)和(2)阐明细胞因子信号，以确定这些药物相互作用的最高风险患者。

项目成果

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.