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使用代谢组学个性化他们的调节方案和/或静脉(IV)白花丹(BU)剂量来提高造血干细胞移植(HCT)接受者的总体存活率。BU是大多数HCT预适应方案的重要组成部分，但治疗指数很低；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血浆暴露与肝毒性增加相关。尽管经常对目标BU暴露进行基于药代动力学(PK)的剂量，但复发和毒性仍然存在问题。此外，较短的静脉输液BU课程需要其他方法来个性化静脉输液BU。然而，IVBU清除率与谷胱甘肽S转移酶A1和GSTM1的多态性无关，这两个基因是BU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，即代谢特征与IVBU清除有关，代谢特征为体内细胞反应和代谢物鉴定提供了新的见解。我们将首先确定在BU给药前获得的基于内源性代谢组学的生物标记物是否可以预测IVBU的清除。我们将使用有针对性的(谷胱甘肽途径)评估内源性生物标记物，并通过液相色谱-质谱学进行全球分析。此外，我们试图利用代谢组学结合气相色谱-质量选择性检测来评估接受基于PK的静脉输注BU的患者的静脉输注BU代谢。我们将根据我们在四氢噻吩(THT+)方面的经验，评估八种不同代谢物的血浆浓度。我们还将评估我们团队刚刚发现的羟色胺，以及最近发现的两种可能导致BU毒性的代谢物：S-谷胱甘肽硫化物(GS+THT)和γ-谷氨酰脱氢丙氨酰甘氨酸(EDAG)。为了补充这项代谢学工作，我们寻求验证与IV BU PK相关的协变量，特别是年龄和身体大小，以缓解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。我们中心自1996年以来一直是基于PK的BU剂量的参考临床实验室，因此，我们拥有最大的IVBU PK数据库。利用群体药代动力学分析，我们将验证IVBU PK的协变量，以指导未来的代谢组学研究。这种PopPK分析可以通过使用协变量更准确地估计静脉输注BU开始剂量(即基于PK的剂量之前)，并通过创建有限的采样计划以更有效地使用基于PK的剂量，从而立即改善患者护理。这些互补的目标寻求识别新的基于代谢组学的生物标记物，可以克服HCT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，我们希望确定一个内源性代谢特征，它将影响静脉输注BU起始剂量的选择，目的是改善接受静脉输注BU-HCT方案的患者的总体存活率。

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.