Clinical Pharmacology of Anticancer Drugs

抗癌药物的临床药理学

• 批准号: 7966037
• 负责人: Frank Balis
• 金额: $ 125.32万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7966037
• 关键词: ABT-751; Adult; Age; Antineoplastic Agents; Arts; BAY 54-9085; Biological Assay; Blood; Blood - brain barrier anatomy; Brain; CCR; Catheters; Central Nervous System Neoplasms; Cerebrospinal Fluid; Child; Childhood; Clinical; Clinical Pharmacology; Clinical Trials; Clinical Trials Design; Correlative Study; Data; Development; Dose; Drug Exposure; Drug Kinetics; Erlotinib; Extracellular Fluid; In Vitro; Incidence; Laboratories; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of central nervous system; Measurement; Measures; Meningeal; Meningeal Neoplasms; Methods; Microdialysis; Modeling; Neuraxis; New Agents; Normal tissue morphology; PXD101; Patients; Pediatric Neoplasm; Penetration; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; Phase I Clinical Trials; Play; Population; Positron-Emission Tomography; Pre-Clinical Model; Research; Research Personnel; Role; Sampling; Satraplatin; Technology; Tissues; Toxic effect; Tumor Cell Line; Ventricular; anakinra; base; blood cerebrospinal fluid barrier; brain tissue; design; drug development; lateral ventricle; nonhuman primate; pre-clinical; tool; tumor

Clinical trials of new agents are studied separately in children because of potential differences in drug disposition and sensitivity to the effects of the drug compared to adults. Therefore, pharmacokinetic and pharmacodynamic studies are an important component of the early phase clinical trials performed in this population. Phase 1 trials performed by the Section include correlative studies to assess the pharmacokinetics of the new agent over a broad age range, and the results of these PK studies are compared directly with adult data and correlated with laboratory and clinical measures of drug effect. The Section has developed new trial designs that have incorporated pharmacologically based endpoints rather than toxicity to determine the optimal dose of new agent s in children. The pharmacokinetics and pharmacodynamics of new agents are also studied in preclinical models. The Section is studying the use of microdialysis as a tool to measure drug exposure in tumors, normal tissues and the blood with plans to extend this technology to patients receiving anticancer drugs. The PET Section provides pharmacological support for clinical trials in the CCR, including designing clinical pharmacokinetic and pharmacodynamic studies, the development of drug assays using a variety of state of the art methods and the measurement of drug concentrations in patient samples, and the analysis of pharmacokinetic and pharmacodynamic data generated by our Section or by pharmaceutical companies. The central nervous system (CNS) pharmacology of anticancer drugs is also studied because of the high incidence and dire consequences of primary and metastatic CNS cancers in children. The CNS pharmacology of anticancer drugs is studied in a non-human primate model with indwelling ventricular catheters that allow for sampling of the cerebrospinal fluid (CSF) and drug administration into the lateral ventricle. Drug penetration into the CSF, which serves as a surrogate measure of blood-brain barrier (BBB) penetration, is used to identify potential new drugs for CNS tumors. Examples of agents recently studied include erlotinib, ABT-751, anakinra, PXD101, talabostat, and O4-benzylfolate, sorafenib, and satraplatin. Microdialysis is also used to measure extracellular fluid drug concentration in brain tissue and to relate brain drug concentration to the drug concentration in other tissues and the cerebrospinal fluid. In addition, strategies to pharmacologically modulate the BBB have been investigated in this model. The preclinical and clinical development of new agents that can be administered intrathecally for the treatment of meningeal tumors is also a focus of research.

与成人相比，由于药物处置的潜在差异和对药物影响的敏感性，新药物的临床试验分别研究了儿童。 因此，药代动力学和药效学研究是该人群进行的早期临床试验的重要组成部分。本节进行的第1阶段试验包括相关研究，以评估广泛年龄范围内新药物的药代动力学，并且这些PK研究的结果与成人数据直接比较，并与实验室和临床药物效应相关。该部分开发了新的试验设计，这些设计纳入了基于药理的终点，而不是毒性，以确定儿童中新药物的最佳剂量。临床前模型还研究了新药物的药代动力学和药效学。该部分正在研究使用微透析作为测量肿瘤，正常组织和血液中药物暴露的工具，并计划将该技术扩展到接受抗癌药物的患者。 PET部分为CCR的临床试验提供了药理学支持，包括设计临床药代动力学和药效学研究，使用各种艺术方法的药物测定开发以及患者样品中药物浓度的测量以及我们部分或药物公司或药物公司生成的药物动力学和药物学数据的分析。还研究了抗癌药物的中枢神经系统（CNS）药理学，因为儿童原发性和转移性中枢神经系统癌的发病率和可怕后果。在非人类灵长类动物模型中研究了抗癌药物的CNS药理学，该模型具有留置心室导管，可将脑脊液（CSF）和药物给药取样到外侧心室中。药物渗透到CSF中，该药物用作血脑屏障（BBB）渗透的替代度量，用于鉴定CNS肿瘤的潜在新药。最近研究的药物的例子包括Erlotinib，ABT-751，Anakinra，PXD101，Talabostat和O4-苯唑酯，索拉非尼和Satraplatin。微透析还用于测量脑组织中的细胞外液药物浓度，并将脑部药物浓度与其他组织的药物浓度和脑脊液浓度相关联。此外，在该模型中研究了药理调节BBB的策略。可以持发式用于治疗脑膜肿瘤的新药物的临床前和临床开发也是研究的重点。

项目成果

Extracellular fluid concentrations of cisplatin, carboplatin, and oxaliplatin in brain, muscle, and blood measured using microdialysis in nonhuman primates.

• DOI: 10.1007/s00280-009-1085-7
• 发表时间: 2010-04
• 期刊: Cancer chemotherapy and pharmacology
• 影响因子: 3
• 作者: Jacobs S;McCully CL;Murphy RF;Bacher J;Balis FM;Fox E
• 通讯作者: Fox E

Plasma and cerebrospinal fluid pharmacokinetics of the histone deacetylase inhibitor, belinostat (PXD101), in non-human primates.

组蛋白脱乙酰酶抑制剂贝利司他 (PXD101) 在非人灵长类动物中的血浆和脑脊液药代动力学。

• DOI: 10.1007/s00280-007-0622-5
• 发表时间: 2008
• 期刊: Cancer chemotherapy and pharmacology
• 影响因子: 3
• 作者: Warren,KatherineE;McCully,Cindy;Dvinge,Henrik;Tjornelund,Jette;Sehested,Maxwell;Lichenstein,HenriS;Balis,FrankM
• 通讯作者: Balis,FrankM