PHARMACOKINETICS AND PHARMACODYNAMICS OF ANTILEUKEMIC AGENTS IN CHILDREN

儿童抗白血病药物的药代动力学和药效学

• 批准号: 6101887
• 负责人: WILLIAM E EVANS
• 金额: --
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-03-15 至 1999-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6101887
• 关键词: acute lymphocytic leukemia; antileukemic agent; biological models; child (0-11); clinical trials; drug administration rate /duration; drug administration routes; drug screening /evaluation; enzyme activity; flow cytometry; folate antagonist; human subject; human therapy evaluation; intracellular; methotrexate; model design /development; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; paclitaxel; pediatric neoplasm /cancer; pharmacokinetics; polyglutamates; prognosis; pyrophosphates; tetrahydrofolylpolyglutamate synthase; tissue /cell culture

The long-term objectives of this project are to characterize the pharmacokinetics (absorption, distribution, metabolism and elimination) of antileukemic drugs in children; to determine patient and/or disease characteristics influencing the disposition of these agents in children; to assess the relation of drug disposition to drug effects (i.e., pharmacodynamics); and to ultimately integrate these data to develop models for establishing optimal dosages and schedules of these drugs for the treatment of childhood leukemia. The pharmacokinetics of anticancer drugs are often significantly different in children when compared to adults, precluding the use of adult pharmacokinetic data to establish optimal dosages for children. Studies here are designed to address three major gaps in our existing knowledge of the pharmacokinetics and pharmacodynamics of antileukemic drugs in children. The first aim addresses whether drug dosage and interpatient variability in drug disposition have a significant effect on the concentration of drug achieved in acute lymphocytic leukemia (ALL) blast cells in vivo. The initial studies will be conducted in newly diagnosed ALL patients randomized to single agent therapy with either high-dose methotrexate (MTX) of low-dose MTX. MTX and its active polyglutamates and folylpolyglutamate synthetase (FPGS) activity will be measured in ALL blasts in vivo, along with biochemical measures of MTX's pharmacologic effects (e.g., PRPP, folates). These will be the first human studies to assess blast cell pharmacokinetics/dynamics in vivo, and will help to define optimal dosages of MTX. The second aim utilizes a novel in vitro method of assessing ALL blast cell sensitivity to each antileukemic agent; it then examines the ratio of systemic exposure to each drug relative to blast cell sensitivity, with the goal of identifying patients at highest risk of relapse. Such data could provide a method for identifying those patients who should be treated with more intensive chemotherapy. the third aim investigates a novel design ("MTSE") for conducting pediatric Phase I trials of new antileukemic agents, in which systemic exposure is escalated instead of drug dosage. The MTSE study has the potential advantage of controlling interpatient pharmacokinetic variability and thereby more precisely defining the maximum level of treatment intensity for future Phase II pediatric trials. Collectively, these studies will contribute substantially to our goal of designing ALL chemotherapy that has maximal efficacy and minimal toxicity.

该项目的长期目标是描述 药物动力学(吸收、分布、代谢和消除) 用于儿童的抗白血病药物；确定患者和/或疾病 影响这些因素在儿童中的倾向的特征； 评估药物处置与药物效果的关系(即， 药效学)；并最终整合这些数据以开发 建立这些药物的最优剂量和时间表的模型 儿童白血病的治疗。抗癌药物的药代动力学研究 与儿童服用药物相比，儿童服用的药物往往有很大不同 成人，排除使用成人药代动力学数据来建立 儿童的最佳剂量。这里的研究旨在解决三个问题 我们对药物动力学和药物动力学现有知识的主要差距 儿童抗白血病药物的药效学研究。第一个目标 解决药物中的药物剂量和患者间变异性 性格特征对药物浓度有显著影响 在体内急性淋巴细胞白血病(ALL)原始细胞中实现。这个 初步研究将在所有新诊断的患者中进行 随机单用大剂量甲氨蝶呤或 小剂量甲氨蝶呤(MTX)。甲氨蝶呤及其活性聚谷氨酸和 将测定所有患者的叶基多谷氨酸合成酶(FPGS)活性 体内爆炸及甲氨蝶呤药理生化测定 影响(例如，PRPP、叶酸)。这将是第一次对人体进行研究 评估母细胞在体内的药代动力学/动力学，将有助于 确定甲氨蝶呤的最佳剂量。第二个目标是利用一种新的体外实验 评估所有原始细胞对每种抗白血病药物敏感性的方法 药物；然后检查全身暴露于每种药物的比率 与原始细胞敏感性相关，目的是识别患者 复发的风险最高。这样的数据可以提供一种方法 确定哪些患者应该接受更多的重症治疗 化疗。第三个目标是研究一种新的设计(“MTSE”) 进行新的抗白血病药物的儿科I期试验，其中 全身暴露是逐步增加的，而不是药物剂量。MTSE研究 具有控制患者间药代动力学的潜在优势 可变性，从而更准确地定义 未来儿科第二阶段试验的治疗强度。总而言之， 这些研究将大大有助于我们设计所有 具有最大疗效和最小毒性的化疗。