ADVL06B1 A PHARMACOKINETIC-PHARMACODYNAMIC PHARMACOGENETIC STUDY OF ACTINOMYCIN-

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 摘要 对于婴儿和幼儿的抗癌药物的最佳剂量，人们基本上缺乏相关知识，从而导致发病率、死亡率和不良结局的风险增加。放线菌素D（Act-D）和长春新碱（VCR）这两种药物特别令人感兴趣，因为对它们的剂量-暴露关系知之甚少。Act-D是一种抗生素类抗肿瘤药物，自20世纪60年代以来一直用于治疗几种儿童癌症。尽管其长期用于儿科肿瘤学，但实际上没有药代动力学（PK）信息可以从中得出安全和适当的基于年龄的儿科给药。这种缺乏基本知识的后果在2002年就很明显，当时儿童肿瘤学小组（COG）在4例放线菌素相关的肝毒性死亡后暂停了3项治疗横纹肌肉瘤儿童的有效方案。Act-D是横纹肌肉瘤和肾母细胞瘤治疗的一个组成部分，尽管在知识上存在差距，但儿科肿瘤学家必须继续使用该药物。VCR是一种抗微管药物，用于治疗许多儿科癌症。神经毒性通常与VCR使用相关，尤其是在3岁以下儿童中。在本研究中，我们将使用经验证的液相色谱/串联质谱（LC/MS/MS）分析法在接受Act-D和VCR治疗的儿童中进行有限采样PK研究，该分析法能够同时定量血浆中的Act-D和VCR，定量下限为0.05 ng/mL。使用标准统计分析和混合效应建模方法，我们将描述Act-D和VCR PK，并确定可能是Act-D和VCR分布决定因素的因素。所得PK模型将用于推导个体患者暴露指标，并描述药物暴露与毒性的相关性。这是一项尝试，旨在开发一种通用的Act-D和VCR给药方案，以最大限度地提高治疗结局并最大限度地降低治疗风险。我们将进一步调查 药物代谢酶和药物转运蛋白的药物遗传学相关性，并确定药物代谢酶和药物转运蛋白的遗传变异与儿童中观察到的药物PK和药效学（PD）之间的相关性。这些研究的结果将增强我们对药物处置、毒性和药理作用的变异性的理解。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT There is a fundamental lack of knowledge regarding optimal dosing of anti-cancer agents for infants and young children, with resultant increased risk of morbidity, mortality, and inferior outcome. Two agents, actinomycin-D (Act-D) and vincristine (VCR) are of particular interest because little is known about their dose-exposure relationships. Act-D, a member of the antibiotic class of anti-neoplastic agents, has been used for the treatment of several childhood cancers since the 1960s. Despite its long-standing use in pediatric oncology, there is virtually no pharmacokinetic (PK) information from which safe and appropriate age-based pediatric dosing can be derived. The consequences of this lack of fundamental knowledge were evident as recently as 2002, when the Childrens Oncology Group (COG) suspended three active protocols for the treatment of children with rhabdomyosarcoma after four actinomycin associated deaths from hepatotoxicity. Act-D is an integral component of rhabdomyosarcoma and Wilms tumor therapy, and pediatric oncologists must continue to administer the drug despite the gap in knowledge. VCR, an anti-microtubule agent, is used in the treatment of many pediatric cancers. Neurotoxicity is commonly associated with VCR use, and is especially concerning in children under three years of age. In this study, we will perform a limited sampling PK study in children being treated with Act-D and VCR, using a validated liquid chromatography/tandem mass spectroscopy (LC/MS/MS) assay capable of simultaneously quantifying Act-D and VCR in plasma to a lower limit of quantification of 0.05 ng/mL. Using both standard statistical analyses and a mixed-effects modeling approach, we will describe Act-D and VCR PK, and identify factors which may be determinants of Act-D and VCR disposition. The resulting PK model will be used to derive individual patient exposure metrics and describe the correlation of drug exposure to toxicity. This is an attempt to develop a universal dosing scheme for Act-D and VCR that maximizes therapeutic outcome and minimizes therapeutic risk. We will additionally investigate pharmacogenetic correlations of drug metabolizing enzymes and drug transporters and determine the correlation between genetic variation in drug metabolizing enzymes and drug transporters and observed drug PK and pharmacodynamics (PD) in children. The results of these studies will enhance our understanding of the variability in drug disposition, toxicity, and pharmacologic effect.