Clinical Pharmacology Approaches towards Accelerating HIV Cure Initiatives

加速艾滋病毒治疗计划的临床药理学方法

基本信息

批准号：
10258039
负责人：
Amelia N Deitchman
金额：
$ 20.12万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-27 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10258039
关键词：
Address Adverse event Age Agonist Amelia Anti-Retroviral Agents Antiviral Agents Antiviral Response Award CD4 Positive T Lymphocytes Cell Cycle Cells Characteristics Chickenpox Chronic Clinical Clinical Pharmacology Clinical Research Clinical Trials Complex DNA DNA Vaccines Data Development Disease Disease remission Doctor of Philosophy Dose Down-Regulation Drug Exposure Drug Interactions Drug Kinetics Exposure to FRAP1 gene Fostering Funding Future Genetic Grant HIV HIV Infections Hematology Herpesvirus Type 3 Heterogeneity Immune Immune System Diseases Immune Targeting Immune response Immunity Immunologic Markers Immunologics Immunology Immunosuppressive Agents Immunotherapeutic agent Individual Inflammation Inflammatory Interruption Investigation K-Series Research Career Programs Knowledge Mentors Mentorship Metabolic Marker Modality Outcome Participant Pathway interactions Patients Pharmaceutical Preparations Pharmacists Pharmacodynamics Pharmacology Pharmacology Study Phenotype RNA Race Recombinants Regimen Research Research Personnel SDZ RAD Safety Sampling Sirolimus T-Cell Activation T-Lymphocyte Therapeutic Time Training Transplant Recipients Up-Regulation VZV vaccine Vaccines Viral Viral Markers Weight Writing Zoster Vaccine antiretroviral therapy career chronic infection clinical translation drug development immune activation immune function immunomodulatory therapies immunoregulation improved inflammatory marker inhibitor/antagonist neutralizing antibody novel novel therapeutic intervention novel therapeutics personalized care pharmacodynamic model pharmacokinetics and pharmacodynamics predicting response preservation programs response sex trait treatment risk trial design vaccine response viral rebound virology

项目摘要

Project Summary/Abstract For the nearly 37 million people living with HIV (PLWH), functional cure, or antiretroviral (ART)-free remission, is rapidly becoming an attainable target. While extensive research on the mechanisms underlying immune dysfunction and viral persistence present promising opportunities for novel therapeutic modalities, a modest understanding of how pharmacology (pharmacokinetics, PK, and pharmacodynamics, PD) contributes to clinical variability in reservoir reduction and immune modulation has frequently resulted in marginal clinical trial outcomes. This career development award will provide Dr. Amelia Deitchman, a pharmacist-researcher with a PhD in PK/PD, with the essential mentorship and training to develop her independent research program to bridge this gap in translational HIV cure research by harnessing heterogeneity in drug response and mismatched clinical translation to further the HIV cure agenda and develop robust and targeted treatments for all patients. Numerous novel therapeutic approaches are being investigated as components of durable HIV cure, including immunosuppressants targeting chronic immune dysfunction and inflammation associated with HIV persistence, as well as broadly neutralizing antibodies (bNAbs) that clear virus and HIV-infected cells. This research investigates the use of sirolimus alone and with Shingrix (recombinant varicella zoster virus, rVZV vaccine) in two clinical trials, and two bNAbs in a combination clinical trial. Using data and samples from these trials in PLWH on virally suppressive ART, and state-of-the-art viral, immune, and pharmacological approaches, the candidate will 1) establish exposure-response of sirolimus and rVZV vaccine on HIV reservoirs, immune function and safety, 2) define predictors of sirolimus and rVZV vaccine response variability attributable to PK and PD heterogeneity, and 3) determine if systemic bNAb levels can predict time to viral rebound after ART interruption in the context of other curative strategies. We hypothesize that changes in outcomes (reservoir size, immune phenotype, inflammatory markers, and for bNAbs, reservoir size and time to viral rebound post ART interruption) are directly related to drug exposure. For sirolimus, these PK/PD relationships may be entirely distinct from those used for other therapeutic indications. Furthermore, we hypothesize that drug-drug interactions, and differences in immune genetics, and patient demographic, clinical, and disease-related traits account for observed variability in clinical drug exposure and response. Ultimately, this award will be the cornerstone for a career in HIV cure clinical pharmacology research through hands-on and didactic training in HIV pharmacology, immunology and virology, clinical trials, and grant writing by an expert team of mentors. These mentors will foster the candidate's development of an independent academic research career answering clinical pharmacology questions in the setting of HIV cure. The research performed as part of this award will support a future R01 submission investigating PK/PD relationships to accelerate drug development, identify novel therapeutic approaches, and deliver precision care to patients.

项目概要/摘要对于近 3700 万艾滋病毒感染者 (PLWH) 的功能性治愈或无需抗逆转录病毒 (ART) 的缓解，正在迅速成为一个可以实现的目标。虽然对免疫机制进行了广泛的研究功能障碍和病毒持续存在为新的治疗方式提供了有希望的机会，适度的了解药理学（药代动力学、PK 和药效学、PD）如何促进临床储存库减少和免疫调节的可变性经常导致临床试验的边缘化结果。该职业发展奖将为药剂师兼研究员 Amelia Deitchman 博士提供 PK/PD 博士，拥有必要的指导和培训来开发她的独立研究项目，以桥接通过利用药物反应的异质性和不匹配的临床，转化艾滋病毒治疗研究中的这一差距推动艾滋病毒治疗议程，并为所有患者开发强有力的、有针对性的治疗方法。正在研究许多新的治疗方法作为持久艾滋病毒治疗的组成部分，包括针对与艾滋病毒相关的慢性免疫功能障碍和炎症的免疫抑制剂持久性，以及清除病毒和 HIV 感染细胞的广泛中和抗体 (bNAb)。这研究调查了西罗莫司单独使用以及与 Shingrix（重组水痘带状疱疹病毒，rVZV 疫苗）在两项临床试验中，以及两种 bNAb 在联合临床试验中。使用来自这些的数据和样本在 PLWH 中进行病毒抑制 ART 试验以及最先进的病毒、免疫和药理学方法，候选人将 1) 建立西罗莫司和 rVZV 疫苗对 HIV 储存库、免疫的暴露反应功能和安全性，2) 定义可归因于 PK 和 rVZV 疫苗反应变异性的西罗莫司和 rVZV 疫苗反应变异性的预测因素 PD 异质性，以及 3) 确定全身 bNAb 水平是否可以预测 ART 后病毒反弹的时间在其他治疗策略的背景下进行中断。我们假设结果发生变化（储层大小、免疫表型、炎症标志物以及 bNAb、储库大小和 ART 后病毒反弹的时间中断）与药物暴露直接相关。对于西罗莫司，这些 PK/PD 关系可能完全是与用于其他治疗适应症的药物不同。此外，我们假设药物-药物免疫遗传学、患者人口统计学、临床和疾病相关特征的相互作用和差异解释观察到的临床药物暴露和反应的变异性。最终，该奖项将成为艾滋病治疗临床药理学研究职业的基石通过艾滋病毒药理学、免疫学和病毒学、临床试验和资助方面的实践和教学培训由专家导师团队撰写。这些导师将促进候选人发展独立的能力学术研究生涯回答艾滋病治疗背景下的临床药理学问题。研究作为该奖项的一部分执行将支持未来 R01 提交调查 PK/PD 关系加速药物开发，确定新的治疗方法，并为患者提供精准护理。