GOLDILOKs: Project 2: Translational

ResponseExposure剂量范例和“暴露量递增”剂量策略将在 GOLDILOKS项目1(临床)高度依赖于个性化给药和实现 在单个儿童的水平上所需的暴露。控制剂量暴露关系 需要适当的药代动力学(PK)模型，该模型考虑了导致 在暴露中观察到的可变性。基于生理的药代动力学(PBPK)模型是 对儿科有相当大的兴趣，因为它们有可能在一年中考虑到多种因素 系统级别。这些变化包括组织体积和成分、器官血液的发育变化 流量、胃酸度、肠道转运时间、蛋白质结合，以及在生长和 发展。在构建和应用PBPK模型时，既有“不确定性”，也有潜在的脆弱性 与可能基于有限数据的参数估计和隐含假设有关--以及 需要考虑“变异性”--个体发育、遗传变异和环境因素。在这 翻译项目，我们将解决与构建个性化基因组相关的几个挑战- 个体发育PK(iGO-PK)模型，为个体患者提供最优ATX剂量 GOLDILOKS倡议。目标1应用短读和长读下一代测序技术 改进CYP2D6基因座内的表型预测并解决远距离单倍型 具有远端(112kb)调节性单核苷酸多态(SNP)和CYP2D6编码区。 通过测定每克肝脏微粒体蛋白的含量并对其个体发育进行表征 (MPPGL)在儿童肝组织中，AIM 2将减少体外培养关键比例因子的不确定性 构成PBPK模型基础的活体外推。在目标2中，我们还建议使用Simcyp PBPK框架和我们的儿科肝库创建一组iGO-PK“虚拟个体”，每个人 利用他们自己独特的基因数据，&gt；50药物的定量(蛋白质)丰度值 代谢酶和转运体以及相应的MPPGL比例因子。我们预料到 根据基因型数据和改进的PBPK模型进行优化的CYP2D6表型预测将导致 改进的儿童剂量个体化给药算法。

The responseexposuredose paradigm and “exposure escalation” dosing strategy to be utilized in GOLDILOKs Project 1 (Clinical) is highly dependent on the ability to individualize dosing and achieve the desired exposure at the level of the individual child. Controlling the doseexposure relationship requires appropriate pharmacokinetic (PK) models that take into consideration factors contributing to the observed variability in exposure. Physiologically based pharmacokinetic (PBPK) models are of considerable interest in pediatrics due to their potential to take multiple factors into consideration at a systems level. These include developmental changes in tissue volumes and composition, organ blood flow, gastric acidity, intestinal transit time, protein binding, among others that occur during growth and development. In building and applying PBPK models, both “uncertainty” – potential vulnerabilities related to parameter estimates and implicit assumptions that may be based on limited data – and “variability” -- ontogeny, genetic variation and environmental factors – need to be considered. In this translational project, we will address several challenges relevant to building individualized Genome- Ontogeny PK (iGO-PK) models to inform optimal ATX dosing for an individual patient within the GOLDILOKs initiative. Aim 1 applies short read and long read next generation sequencing technology to refine phenotype predictions within the CYP2D6 gene locus and to resolve long range haplotypes with a distal (112kb) regulatory single nucleotide polymorphism (SNP) and the CYP2D6 coding region. By determining the content and characterizing the ontogeny of microsomal protein per gram liver (MPPGL) in pediatric liver tissue, Aim 2 will reduce uncertainty in a critical scaling factor for in vitro-in vivo extrapolations that form the basis of PBPK models. In Aim 2 we also propose to use the Simcyp PBPK framework and our pediatric liver bank to create a group of iGO-PK “virtual individuals”, each with their own unique genotype data, quantitative (proteomic) abundance values for >50 drug metabolizing enzymes and transporters and corresponding MPPGL scaling factor. We anticipate that optimized CYP2D6 phenotype prediction from genotype data and improved PBPK models will result in improved dosing algorithms for dose individualization in children.