Optimizing Busulfan: Efficacy Toxicity and Pharmacometabolomics

优化白消安：功效、毒性和药物代谢组学

• 批准号: 9315780
• 负责人: Jeannine S McCune
• 金额: $ 51.5万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9315780
• 关键词: Adult; Age; Alkylating Agents; Allogenic; Biological; Biological Markers; Body Size; Busulfan; Childhood; Clinical; Complement; Conflict (Psychology); Constitutional; DNA; Data; Databases; Detection; Disease; Dose; Drug Kinetics; Equilibrium; Fatty acid glycerol esters; Future; GSTA1 gene; GSTA1-1 gene; GSTM1 gene; GSTP1 gene; Gas Chromatography; Gender; Genetic Polymorphism; Genotype; Glutathione; Glutathione S-Transferase; Goals; Hematopoietic Stem Cell Transplantation; Hepatotoxicity; In Vitro; Intention; Intravenous; Ions; Isoenzymes; Laboratories; Liquid substance; Malignant - descriptor; Mass Chromatography; Mesylates; Metabolism; Methods; Minor; Modeling; Non-Malignant; Outcome; Oxides; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Pharmacometabolomics; Plasma; Population; Prospective cohort; Regimen; Relapse; Research; Risk; Role; Route; Sampling; Schedule; Testing; Therapeutic Index; Time; Toxic effect; Transplant Recipients; Whole-Body Irradiation; Work; aqueous; base; cohort; conditioning; curative treatments; drug metabolism; experience; glutathione S-transferase M1; hematopoietic cell transplantation; improved; in vivo; insight; interest; liquid chromatography mass spectrometry; liquid chromatography mass spectroscopy; metabolomics; mortality; novel; personalized medicine; pharmacokinetic model; pre-clinical; predictive marker; primary outcome; prospective; public health relevance; response; small molecule; tetrahydrothiophene; tool

DESCRIPTION (provided by applicant): The long-range goal of this work is to improve overall survival in hematopoietic stem cell transplant (HCT) recipients by personalizing their conditioning regimen and/or intravenous (IV) busulfan (BU) doses using metabolomics. BU is an essential part of the majority of HCT conditioning regimens, but has a narrow therapeutic index; low BU plasma exposure (caused by rapid clearance) is associated with an increased risk of rejection or relapse, while high BU plasma exposure is associated with an increased risk of hepatotoxicity. Although pharmacokinetic (PK)-based dosing to a target BU exposure is often conducted, relapse and toxicity continue to be problematic. Furthermore, shorter IV BU courses necessitate alternative methods to personalize IV BU. IV BU clearance, however, is not associated with polymorphisms of glutathione S-transferase (GST) A1 and GSTM1, the predominant GSTs in BU conjugation with glutathione. Therefore, we seek to test our working hypothesis that metabolomic signature, which provides novel insight into the in vivo cellular response and metabolite identification, is associated with IV BU clearance. We will first determine if endogenous metabolomics-based biomarkers obtained before BU administration can predict IV BU clearance. We will evaluate endogenous biomarkers using a targeted (glutathione pathway) and global analyses via liquid chromatography-mass spectroscopy. In addition, we seek to evaluate IV BU metabolism using metabolomics in parallel with gas chromatography-mass selective detection in patients receiving PK-based IV BU. We will evaluate plasma concentrations of eight different metabolites, building upon our experience with tetrahydrothiophene (THT+). We will also evaluate hydroxyTHT, which was just discovered by our group, and two recently identified metabolites that may contribute to BU toxicity: S-glutathione sulfonium conjugate (GS+THT) and γ-glutamyldehydroalanylglycine (EdAG). To complement this metabolomic work, we seek to validate covariates associated with IV BU PK, specifically age and body size, to mitigate a typical challenge for metabolomics research: the lack of understanding of potentially confounding factors. Our center has been a reference clinical laboratory for PK-based BU dosing since 1996 and thus, we have the largest database of IV BU PK. Using population pharmacokinetic (popPK) analysis, we will validate covariates for IV BU PK to guide future metabolomic studies. This popPK analysis can immediately improve patient care by using covariates to more accurately estimate an IV BU starting dose (i.e., before PK-based dosing) and by creating a limited sampling schedule to more efficiently use PK-based dosing. These complementary aims, which seek to identify novel metabolomics-based biomarkers, could overcome a critical barrier to HCT conditioning of balancing between response and toxicity. Based on our compelling preliminary data, we expect to identify an endogenous metabolomic signature that will influence the choice of an IV BU starting dose with the intention of improving overall survival for patients receiving IV BU-containing HCT regimens.

描述（由申请人提供）：这项工作的长期目标是通过使用代谢组学个性化预处理方案和/或静脉内（IV）白消安（BU）剂量来改善造血干细胞移植（HCT）受者的总生存率。BU是大多数HCT预处理方案的重要组成部分，但治疗指数较窄;低BU血浆暴露（由快速清除引起）与排斥或复发风险增加相关，而高BU血浆暴露与肝毒性风险增加相关。尽管经常进行基于药代动力学（PK）的目标BU暴露给药，但复发和毒性仍然存在问题。此外，较短的IV BU课程需要替代方法来个性化IV BU。然而，IV BU清除率与谷胱甘肽S-转移酶（GST）A1和GSTM 1的多态性无关，这是BU与谷胱甘肽结合的主要GST。因此，我们试图检验我们的工作假设，即代谢组学特征与IV BU清除率相关，代谢组学特征为体内细胞反应和代谢物鉴定提供了新的见解。我们将首先确定BU给药前获得的基于内源性代谢组学的生物标志物是否可以预测IV BU清除率。我们将通过液相色谱-质谱法使用靶向（谷胱甘肽途径）和全局分析来评估内源性生物标志物。此外，我们试图在接受PK为基础的IV BU的患者中，使用代谢组学与气相色谱-质量选择性检测并行评估IV BU代谢。我们将根据我们的四氢噻吩（THT+）经验，评价8种不同代谢物的血浆浓度。我们还将评估我们小组刚刚发现的羟基THT和两种最近发现的可能导致BU毒性的代谢产物：S-谷胱甘肽锍结合物（GS+THT）和γ-谷氨酰脱氢丙氨酰甘氨酸（EdAG）。为了补充这项代谢组学工作，我们试图验证与IV BU PK相关的协变量，特别是年龄和体型，以减轻代谢组学研究的典型挑战：缺乏对潜在混杂因素的了解。自1996年以来，我们中心一直是基于PK的BU给药的参考临床实验室，因此，我们拥有最大的IV BU PK数据库。使用群体药代动力学（popPK）分析，我们将验证IV BU PK的协变量，以指导未来的代谢组学研究。该popPK分析可通过使用协变量更准确地估计IV BU起始剂量（即，在基于PK的给药之前），并通过创建有限的采样时间表来更有效地使用基于PK的给药。这些互补的目标，寻求确定新的代谢组学为基础的生物标志物，可以克服一个关键的障碍，HCT调节反应和毒性之间的平衡。基于我们令人信服的初步数据，我们期望确定一种内源性代谢组学特征，该特征将影响IV BU起始剂量的选择，目的是改善接受含IV BU HCT方案的患者的总生存期。