Optimizing Busulfan: Efficacy Toxicity and Pharmacometabolomics

描述（由申请人提供）：这项工作的长期目标是通过代谢组学个性化他们的调节方案和/或静脉注射（IV） busulfan （BU）剂量来提高造血干细胞移植（HCT）接受者的总体生存率。布鲁里溃疡是大多数HCT调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有关，而高BU血浆暴露与肝毒性风险增加有关。虽然经常进行基于药代动力学（PK）的靶BU暴露剂量，但复发和毒性仍然是一个问题。此外，较短的静脉注射治疗需要个性化静脉注射治疗的替代方法。然而，IV型布鲁里溃疡清除与谷胱甘肽s -转移酶（GST） A1和GSTM1的多态性无关，GST是布鲁里溃疡与谷胱甘肽结合的主要GST。因此，我们试图验证我们的工作假设，即代谢组学特征与IV BU清除有关，这为体内细胞反应和代谢物鉴定提供了新的见解。我们将首先确定在给药前获得的内源性代谢组学生物标志物是否可以预测IV型布鲁里菌清除。我们将使用靶向（谷胱甘肽途径）和液相色谱-质谱分析来评估内源性生物标志物。此外，我们试图利用代谢组学与气相色谱-质量选择性检测相结合的方法来评估IV型BU的代谢。我们将根据四氢噻吩（THT+）的经验，评估八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THT，以及最近发现的两种可能导致BU毒性的代谢物：s -谷胱甘肽磺酸缀合物（GS+THT）和γ-谷氨酰脱氢丙酰甘氨酸（EdAG）。为了补充代谢组学研究，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一个典型挑战：缺乏对潜在混杂因素的理解。自1996年以来，本中心一直是基于钾的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。popPK分析可以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计划来更有效地使用基于pk的给药，从而立即改善患者护理。这些互补的目标，寻求鉴定新的基于代谢组学的生物标志物，可以克服HCT调节在反应和毒性之间平衡的关键障碍。基于我们令人信服的初步数据，我们期望确定内源性代谢组学特征，该特征将影响IV BU起始剂量的选择，目的是提高接受IV BU含HCT方案的患者的总生存率。

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.