DCTD Human Toxicology and Pharmacology

DCTD 人类毒理学和药理学

• 批准号: 8008848
• 负责人: LARRY ARTHUR
• 金额: $ 755.4万
• 依托单位: LEIDOS BIOMEDICAL RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-26 至 2018-09-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8008848
• 关键词: Acute; Adenovirus Vector; Adenoviruses; Adopted; Adverse drug effect; Adverse effects; Affect; Anesthesia procedures; Animal Model; Animals; Apoptosis; Area; Biological Assay; Biological Markers; Biological Testing; Biopsy; Bone Marrow; CCR; Cancer Model; Canis familiaris; Cardiotoxicity; Carrier Proteins; Cell Culture Techniques; Cells; Characteristics; Chemicals; Chronic; Clinic; Clinical; Clinical Trials; Clinical assessments; Collaborations; Combined Modality Therapy; Companions; Contractor; Custom; Data; Dependency; Development; Developmental Therapeutics Program; Dosage Forms; Dose; Dose-Limiting; Drug Delivery Systems; Drug Evaluation; Drug Exposure; Drug Formulations; Drug Kinetics; Drug Monitoring; Drug Tolerance; Drug effect disorder; Drug toxicity; Effectiveness; Emulsions; Engineering; Equilibrium; Evaluable Disease; Evaluation; Excision biopsy; Exhibits; Exposure to; Failure; Foundations; Future; Goals; Grant; Guidelines; Hepatic; Hepatocyte; Hepatotoxicity; Human; Image; In Vitro; Injection of therapeutic agent; Intravenous; Investigation; Knowledge; Laboratories; Lead; Learning; Lesion; Liquid substance; Liver; Lung; Malignant Neoplasms; Maximum Tolerated Dose; Measles; Mediating; Medical; Men' s Role; Methodology; Methods; Mission; Modality; Modeling; Molecular; Molecular Target; Monitor; Mus; Myeloid Progenitor Cells; Needles; Nerve Tissue; Neutropenia; Normal tissue morphology; Oncolytic; Operative Surgical Procedures; Oral Administration; Oral mucous membrane structure; Organ; Outcome; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmaceutical Technology; Pharmacodynamics; Pharmacology and Toxicology; Phase; Physiological; Plasma; Play; Poliomyelitis; Pre-Clinical Model; Procedures; Process; Program Development; Proximal Kidney Tubules; Radiation; Readiness; Recombinants; Reovirus 3; Reporter; Reporting; Research; Research Design; Rodent; Role; Route; Safety; Saliva; Sampling; Schedule; Screening procedure; Signal Transduction; Skin; Solubility; Specimen; Staging; Supervision; Symptoms; System; Technology; Testing; Therapeutic; Therapeutic Agents; Tissue Banks; Tissue Sample; Tissues; Toxic effect; Toxicity Tests; Toxicology; Training; Translational Research; Translations; Treatment Protocols; Tumor Cell Line; Tumor Tissue; Uncertainty; United States National Institutes of Health; Validation; Viral; Viral Load result; Viral Vector; Virus; Work; Xenograft Model; Xenograft procedure; analog; aqueous; assay development; base; body system; cancer cell; cancer therapy; cell type; chemotherapeutic agent; chemotherapy; clinical assay development; clinically relevant; cytotoxic; design; drug candidate; drug development; drug discovery; efficacy evaluation; functional status; gastrointestinal; human disease; human tissue; improved; in vitro Assay; in vitro Model; in vitro testing; in vivo; in vivo Model; innovation; interest; intravenous injection; keratinocyte; man; melanoma; mouse model; nanoparticle; new technology; novel; oncology; oncolysis; operation; pre-clinical; preclinical efficacy; preclinical evaluation; preclinical study; programs; research clinical testing; response; safety engineering; small molecule; tissue culture; tool; toxicant; tumor; vector

Laboratory of Human Toxicology and Pharmacology (LHTP) - The Laboratory of Human Toxicology and Pharmacology (LHTP) provides technical and operational support for DCTD programs designed to increase the pace and accuracy of drug development in oncology and facilitate the entry of new chemical entities (NCEs) for cancer treatment into Phase 0 and I clinical trials. LHTP is an integrated, multi-disciplinary laboratory program that builds on the foundation of pharmacodynamics (PD) and toxicodynamics (TD) to predict the desirable and undesirable human drug effects that will likely be encountered during the clinical evaluation of both traditional cytotoxic as well as newer molecular target based small molecules and engineered therapeutic viruses. LHTP expertise in predictive human toxicology using in vitro models, pharmacodynamic assay development and clinical implementation, and preclinical drug formulation combine to humanize treatment regimens, therapeutic assessment, and interpretation of non-clinical models of cancer. The laboratory integrates this novel expertise to ¿humanize¿ treatment and assessment of mouse models of human disease in order to validate pharmacodynamic assays for use as primary endpoints of Phase 0 trials, which are conducted under exploratory IND guidelines from the FDA to confirm that a NCE works in man as it has in the preclinical models. The integrated approach includes a route of administration, dosage form, dose level, and clinical sampling procedures (e.g., anesthesia, needle, or excisional biopsy) that are directly relevant to a Phase 0 clinical trial. The LHTP introduced the concept and practice of completely humanizing preclinical models of cancer therapy, which led to the use of clinical biopsy procedures in human xenograft and orthotopic tumor models to prove the clinical readiness of a PD assay. LHTP took the lead in ¿reverse translational¿ research, to learn the clinical procedures of tissue collection and then transfer them to DTP/BTB. Comparing humanized and traditional preclinical study designs in cancer models over several years will yield the results required to determine whether this approach improves the correlation between nonclinical models and the clinic. The LHTP is organized into four specialized, but interrelated, sections that align with the technical support needs of DCTD: Pharmacodynamic Assay Development and Implementation (PADIS), Predictive Toxicology (PTS), Viral Vector Toxicology (VVTS), and Formulation Development (FDS). The laboratory director manages the overall scientific program of the LHTP and its coordination with DCTD operations, including coordinated interactions and assay transfers from LHTP to the National Clinical Target Validation Laboratory (NCTVL) operating at the NIH campus. Pharmacodynamic Assay Development and Implementation Section (PADIS) - Modern developmental therapeutic efforts for cancer utilize an understanding of signal transduction or differentiation pathways to identify new drug candidates that exert defined actions on the functional status of these targets. Some of these defined molecular effects will have therapeutic potential, leading to apoptosis, differentiation, or other desirable changes in the function of cancer cells. By coordinated use of the preclinical efficacy models of the Biological Testing Branch of DTP, it is possible to define the relationship between the extent of drug effect in the tumor and the level of drug exposure associated with these effects. Clinical confirmation of these preclinical findings would provide strong rationale for a full clinical development program, and the FDA recently authorized a new type of early clinical trial to explore microdoses of investigational agents prior to full dose finding and safety trials. This exploratory IND mechanism (x-IND) is relevant for multiple therapeutic classes, and is being used by the DCTD to conduct such confirmatory studies of molecular drug action on tumor target in a small number of patients prior to full clinical development (termed ¿Phase 0 trials¿ at the NCI). Failure of a NCE to affect molecular target during the Phase 0 trial would provide a rationale to halt its development. The mission of PADIS is to provide expert technical support to this DCTD initiative by developing and validating laboratory assays that quantify a drug's effect on a molecular target in a tumor (and, if possible, in surrogate tissues as well), and can be readily implemented in the clinical setting. PADIS uses preclinical models to develop and validate pharmacodynamic (PD) assays and companion procedures for tissue acquisition that will be used in the clinical trial without change. A unique aspect of the PADIS approach is the constraints imposed on the development and validation of PD assays by the radiological, surgical, and anesthesia procedures and practices that will eventually be used clinically to obtain the tissue specimens for the PD assays. This is a technical area that has been underappreciated in the past, and PADIS works closely with BTB to integrate anticipated medical procedures into the preclinical models and develop clinically ready assays. When they can be established as accurate reporters of drug action in tumor, surrogate organ compartments (such as peripheral blood mononuclear cells or bone marrow or buccal keratinocytes) are useful for less invasive monitoring of drug effects than biopsies. As the final step in PD assay development and implementation, PADIS is responsible for cross-training the Bethesda-based NCTVL staff in the new assays and then coordinating with NCTVL to transfer the validated method to the clinical laboratory for deployment in the x-IND clinical trial. PADIS plays a key technical role in the developmental stages of clinical pharmacodynamic projects of the DCTD and its collaboration with the CCR in Phase 0 clinical trials. These stages can be summarized as: rapid development and validation of sensitive, SOP-driven methodologies to quantify the impact of drug treatment on molecular target(s) in tumors; identification of normal tissue that is a surrogate for tumor, if possible (PBMCs, skin, saliva, buccal mucosa, etc); development and validation of clinically-transferable, SOP-driven procedures for tissue collection and processing that will provide evaluable specimens in the clinical setting; and oversee the transfer of validated PD assays to the NCTVL for deployment in clinical trials, and if necessary, contribute to assays of clinical specimens. Predictive Toxicology Section (PTS) - The Predictive Toxicology Section (PTS) was established to facilitate the maturation and validation of assays that have been shown to predict human toxicity, and deploy them in concert with pharmacokinetic (PK)/ pharmacodynamic (PD) programs in the DTP to facilitate development of NCEs more efficiently and accurately for potential advancement to clinical trials. Preclinical toxicology studies on potential cancer chemotherapeutic agents are generally conducted in two species of animals with the goals of defining the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), schedule dependency of toxicity, reversibility of adverse effects, and a safe clinical starting dose (SD). These animal studies do not always permit detailed evaluations of molecular toxicity, especially in relation to the expected mechanism in man and the role of off-target effects in mediating toxicity. Furthermore, the in vivo data sometimes show discrepancies between species that create uncertainty about human safety and result in low starting doses in early clinical trials. The PTS is tasked with the development of in vitro tissue, cellular, and molecular assays that use normal target tissues of drug toxicity and clinically relevant endpoints (e.g., in vitro ¿transaminitis¿) to evaluate potential human safety, predict tolerated human doses, and allow direct comparison of human and animal drug tolerance prior to clinical trials. This information can be used to include predicted human tolerated dose levels into studies by PADIS to validate PD assays at predicted clinical dose levels, increasing confidence that a target response to the drug will be detected clinically. The recent validation of in vitro bone marrow assays for neutropenia using rodent, canine, and human CFU-GM myeloid stem cells demonstrated the value of in vitro assays for predicting in vivo toxicities in animals and man. The PTS seeks to extend the application of the validated testing principles to other dose-limiting organ system toxicities, including pulmonary, hepatic, and cardiac toxicities. In addition, PTS is tasked with assisting the Toxicology and Pharmacology Branch, DTP in its evaluation of newly developed in vitro toxicity tests under its grant program entitled ¿Innovative Toxicology Models for Drug Evaluation¿ and the importing of promising assays into PTS for validation. The in vitro models of normal tissue response to adverse drug effects are expected to provide a simpler system than the in vivo models used for the discovery of off-target drug effects that can be circumvented via analoging and toxicodynamic markers of organ toxicity, which become candidates for valid assay development by PADIS and used by medical laboratories to monitor for early stages of drug toxicity prior to the development of symptoms. Newly developed in vitro assays are validated and then transferred to the VVTS for specialized applications in the assessment of human safety of engineered viral therapeutics (see below). These novel safety assessment tools can be deployed in the pre-IND or IND-directed setting. Viral Vector Toxicology Section (VVTS) - The primary mission of the VVTS is to provide support for preclinical development of anticancer viral vectors. The research efforts are currently focused on the investigation of human toxicity potential of novel anticancer viral vectors by using humanized in vitro assay systems, and the evaluation of oncolytic activity and tumor selectivity of cancer-targeting viral vector agents. The VVTS explores the potential application of newly developed toxicity tests in PTS to the in vitro human safety assessment of engineered viral therapeutics. Additional areas of research include the assessment of the feasibility and efficacy of anticancer vector-combination therapy, consisting of viral vector agents and other cancer treatments of different modalities (e.g., chemotherapy or radiation); the elucidation of the molecular basis of tumor selection and oncolysis by candidate viral vectors; identification and establishment of tumor-specific biomarkers of viral agent-susceptible cancers, which can be adopted for future in vivo applications; and the development of optimal viral burden quantification assays to monitor the replication of viral vectors in targeted (tumor) and non-targeted (normal) tissue compartments in conjunction with in vivo safety and/or efficacy evaluations. During the reporting period, VVTS established a new in vitro assay system to evaluate the hepatotoxic potential of adenovirus-based anticancer vectors using primary human hepatocytes, characterized differential hepatotoxicity profiles of recombinant adenoviral vectors developed as therapeutic agents under the RAID program, and began collaboration with Biological Testing Branch (BTB), DTP, to evaluate the in vivo efficacy of oncolytic reovirus type 3 Dearing strain in a human melanoma xenograft model. Formulation Development Section Many NCEs that show promising anticancer characteristics exhibit very low aqueous solubility, which creates technical difficulties during in vitro and in vivo evaluations. The Formulation Development Section (FDS) is tasked with development of preclinical formulations of these NCEs suitable for intravenous injection and oral administration to mice and dogs and for testing in vitro in cell cultures. The FDS is developing a novel, moderate-throughput strategy comprised of an initial empirical screen, using 2¿5 mg of each NCE, to test for solubility in a dozen proven vehicles representing diverse solubilizing mechanisms, which have been used clinically. Suitability of these candidate pre-formulations for injection is proven by continued solubility when challenged with physiological fluids. It is expected that 10¿20% of poorly soluble NCEs will not be solubilized by conventional vehicles, and so the next step in the strategy is formulation testing of NCEs in novel pharmaceutical technology platforms, such as nanodispersions and emulsions, targeted nano-particles, and targeted carrier proteins. Although not all NCEs will have been formulatable by the end of the second step, this strategy is expected to achieve solubility and consistency requirements for in vitro studies of efficacy in the DTP screen and of in vitro human toxicity by PTS with a large majority of NCEs in the DTP pipeline. A large number of these formulated NCEs will also be suitable for intravenous and oral administration in animal models: BTB efficacy studies, BTB and TPB studies of PK and PD including validation of molecular PD assays by PADIS, and PTS assessment of toxicity via biomarkers (PTS) or clinical assessment. These preclinical formulations are intended to facilitate preclinical evaluation of developmental compounds, and are not necessarily the same as the formulated clinical product that may advance into clinical trials.

人类毒理学和药理学实验室（LHTP） - 人类毒理学和药理学实验室（LHTP）为DCTD计划提供了技术和运营支持，旨在提高肿瘤学中药物开发的步伐和准确性，并支持新化学实体（NCES）进入0阶段和I期临床试验的新化学实体（NCE）。 LHTP是一项综合的多学科实验室计划，基于药物动力学（PD）和毒性动力学（TD）的基础，可预测在传统的细胞毒性和新型细胞靶标的临床评估期间可能会遇到的可取和不受欢迎的人类药物效应，以及较新的基于分子的小型分子和培训型。 LHTP使用体外模型，药效学评估开发和临床实施以及临床前药物配方组合的LHTP专业知识，以人性化治疗方案，治疗评估以及对非临床癌症模型的解释。实验室将这种新颖的专业知识融入了人性化的治疗和评估人类疾病的小鼠模型，以验证药物大型动力学测定法，以用作第0期试验的主要终点，这些试验是根据FDA的探索性IND指南进行的，以确认在急诊模型中具有NECE的作品。综合方法包括一种与0期临床试验直接相关的给药途径，剂型，剂量水平和临床抽样程序（例如麻醉，针或移动活检）。 LHTP介绍了癌症治疗的临床前模型的概念和实践，这导致在人异种移植物和原位肿瘤模型中使用临床活检程序来证明PD分析的临床准备就绪。 LHTP领导着逆转转化研究，学习组织收集的临床程序，然后将其转移到DTP/BTB。比较几年来癌症模型中人性化和传统的临床前研究设计将产生确定这种方法是否改善非临床模型与诊所之间的相关性所需的结果。 LHTP分为四个专业但相互关联的部分，这些部分与DCTD的技术支持需求：药效学测定开发和实施（PADIS），预测毒理学（PTS），病毒载体毒理学（VVTS）和形成开发（FDS）（FDS）。实验室主管管理LHTP的整体科学计划及其与DCTD操作的协调，包括协调的相互作用和从LHTP到NIH校园运营的国家临床目标验证实验室（NCTVL）的测定转移。 药学分析开发和实施部分（PADIS） - 现代发展的癌症治疗努力利用对信号传递或分化途径的理解来确定对这些目标的功能状态执行定义的候选候选者。这些定义的分子作用中的一些将具有治疗潜力，从而导致癌细胞功能的细胞凋亡，分化或其他理想的变化。通过对DTP生物测试分支的临床前有效性模型的协调使用，对这些临床前发现的临床证实将为完整的临床开发计划提供强大的理由，而FDA最近授权了一种新型的早期临床试验来探索在完整剂量发现和安全试验之前的研究性药物的微剂量。这种探索性IND机制（X-IND）与多种治疗类别有关，DCTD正在使用少数患者在全面临床发育之前对分子药物作用对肿瘤靶靶标的分子药物作用进行此类确认研究（称为NCI的0阶段试验€）。在0阶段试验期间，NCE未能影响分子靶标，将提供一个理由，以阻止其发展。 PADIS的任务是通过开发和验证实验室测定法为该DCTD倡议提供专家的技术支持，从而量化药物对肿瘤中分子靶标的影响（以及在可能的情况下，也可以在替代组织中），并且可以在临床环境中很容易实施。 Padis使用临床前模型来开发和验证用于组织采集的药物脱粒动力学（PD）测定法和伴随程序，这些方法将在临床试验中使用而不会改变。 PADIS方法的一个独特方面是对放射线，外科和麻醉程序和实践对PD测定的开发和验证的限制，这些程序最终将在临床上用于获得PD分析的组织标本。这是一个过去的技术领域。当可以将它们确定为肿瘤中药物作用的准确记者时，替代器官室（例如外周血单核细胞，骨髓或颊角质形成细胞）比生物效应的侵入性较小。作为PD分析开发和实施的最后一步，PADIS负责在新测定中对基于Bethesda的NCTVL员工进行交叉培训，然后与NCTVL协调，以将有效的方法转移到X-IND临床试验中的临床实验室中进行部署。 Padis在DCTD的临床药效项目的发育阶段及其与CCR的合作在0阶段临床试验中起关键的技术作用。这些阶段可以总结为：快速开发和验证敏感的SOP驱动方法，以量化药物治疗对肿瘤分子靶靶的影响；如果可能的话，可以鉴定正常组织，该组织是肿瘤的替代物（PBMC，皮肤，唾液，颊粘膜等）；临床转移，SOP驱动的开发和验证 组织收集和加工的程序，这些程序将在临床环境中提供有价值的标本；并监督经过验证的PD分析转移到NCTVL进行临床试验中的部署，并在必要时有助于临床样本的测定。 预测毒理学部分（PTS） - 建立了“预测毒理学”部分（PTS），以促进已证明可以预测人类毒性的测定的成熟和验证，并与DTP中的药物（PK）/药物（PK）/药物（PK）/药物（PK）/ Pharmacovericanic（PD）计划进行部署，以在DTP中进行更大的效率和临床的发展，以提高有效的效果和准确的ADCE。临床前毒理学研究对潜在癌症化学治疗剂的研究通常在两种动物中进行，其目标是定义最大耐受剂量（MTD），剂量限制毒性（DLT），毒性的进度依赖性，不良影响的毒性依赖性，不良影响和安全的临床开始剂量（SD）。这些动物研究并不总是允许对分子毒性进行详细评估，尤其是与人类的预期机制以及脱靶作用在介导毒性中的作用有关。此外，体内数据有时会显示出对人类安全的不确定性的差异，并在早期临床试验中导致起始剂量低。 PT的任务是使用正常的药物毒性和临床相关终点（例如，体外跨氨基炎）来评估潜在的人类安全性，预测人类剂量的人类剂量，并可以直接比较人类和动物药物的临床试验，以评估潜在的人类安全剂量。该信息可用于将预测的人类耐受剂量水平包括在PADIS的研究中，以在预测的临床剂量水平下验证PD分析，从而增加了对将在临床上检测到对药物的目标反应的信心。最近使用啮齿动物，犬和人CFU-GM髓样干细胞对体外骨髓测定法的验证证明了体外评估的价值，以预测动物和人体内毒性。 PTS试图将经过验证的测试原理的应用扩展到其他限制器官系统毒性，包括肺，肝和心脏毒性。此外，PTS的任务是协助毒理学和药理学分支，DTP评估其在其赠款计划下的新开发的体外毒性测试的评估，其标题为“创新毒理学模型”，用于药物评估，并将承诺的驴子进口到PTS中进行验证。与用于发现脱靶药物效应的体内模型相比，正常组织对不良药物作用的反应的体外模型可以提供更简单的系统，这些模型可以通过类比和器官毒性的毒性标志物来避免，该模型可用于候选，该标志物成为PADIS开发的候选者，可用于PADIS的有效评估，并用于医疗实验室的早期阶段，以使早期的药物毒性具有症状的早期毒性症状。新开发的体外测定法经过验证，然后转移到VVTs，以评估工程病毒疗法的人体安全时（见下文）。这些新型的安全评估工具可以部署在预先指定或指定的环境中。 病毒载体毒理学部分（VVTS） - VVTS的主要任务是为抗癌病毒载体的临床前发展提供支持。目前，通过使用人性化的体外评估系统以及评估溶瘤活性和癌靶向病毒载体的肿瘤选择性的评估，研究工作目前侧重于研究新型抗癌病毒载体的人类毒性潜力。 VVTS探讨了新开发的PTS中新开发的毒性测试在工程病毒疗法的体外人体安全评估中的潜在应用。其他研究领域包括评估抗癌载体 - 组合疗法的可行性和效率，包括病毒载体剂和其他不同方式（例如化学疗法或放射线）的其他癌症治疗；通过候选病毒向量阐明肿瘤选择和肿瘤分解的分子基础；鉴定和建立病毒剂造成癌症的肿瘤特异性生物标志物，这些癌症可用于未来的体内应用；以及最佳病毒负担定量测定法的开发，以监测靶向（肿瘤）和非靶向（正常）组织室中病毒载体的复制，并结合体内安全性和/或有效性评估。在报告期间，VVTS建立了一种新的体外评估系统，以使用原发性人肝细胞来评估基于腺病毒的抗癌媒介的肝毒性潜力，表征了重组腺病毒载体的差异性肝毒性谱，该腺病毒载体是在重组腺病毒载体中开发的，该腺病毒载体是根据生物培养的，是在生物上与生物进行了测试，并在生物上进行了测试（btt of test of test of test of test of tositigy drogipt​​ ost drogiped drogipt​​ ost drogiped drogipt​​ ost drogiped drogiped drogip of test of tositigation drogiped dody drogy dodtep（人黑色素瘤特征模型中的溶瘤蒸发病毒3型可爱菌株的体内效率。 配方开发部分 许多显示出有希望的抗癌特征的人表现出非常低的水溶性，这在体外和体内评估过程中造成了技术困难。配方开发部分（FDS）的任务是开发这些NCE的临床前公式，适合于静脉注射和口服对小鼠和狗的口服，并在细胞培养物中进行体外测试。 FDS正在使用每种NCE 2毫克的初始经验屏幕制定一种新颖的，中等的促进策略，以测试代表临床上使用的不同可溶性机制的十二个验证的可溶性车辆的溶解化。这些候选者预先制定注射的适用性是通过挑战物理流体挑战的持续溶解度来证明的。可以预期，传统车辆的可溶性不足的NCE中有10％的溶解度不会溶于溶解性，因此该策略的下一步是在新型药物技术平台中制定NCES的测试，例如纳米分散和乳液，靶向纳米颗粒和靶向载体蛋白。尽管并非所有的NCE都可以在第二步结束时进行公式化，但预计该策略将对DTP筛查中效率的体外研究以及DTP管道中大部分NCE的PTS的体外人类毒性实现可溶性和一致性要求。在动物模型中，大量这些配制的NCE也将适用于静脉和口服的静脉内和口服：BTB效率研究，PK和PD的BTB效率研究，BTB和TPB研究，包括PADIS通过PADIS验证分子PD测定，以及PTS通过生物标志物（PTS）或临床评估对毒性评估。这些临床前公式旨在促进对发育化合物的临床前评估，并且与可能进步临床试验的正式临床产品相同。