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 ?-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.
The goal of these studies is to identify patient-specific factors related to how a patient's body breaks down intravenous busulfan, which is commonly used prior to hematopoietic stem cell transplantation. Using a new personalized medicine tool called metabolomics, we will evaluate small molecule metabolites found in a patient's plasma before and after busulfan administration. We will confirm that patient-specific factors, specifically age and body size, influence how a patient's body breaks down busulfan.
|Johnson, Emily J; González-Peréz, Vanessa; Tian, Dan-Dan et al. (2018) Selection of Priority Natural Products for Evaluation as Potential Precipitants of Natural Product-Drug Interactions: A NaPDI Center Recommended Approach. Drug Metab Dispos 46:1046-1052|
|Lin, Yvonne S; Kerr, Savannah J; Randolph, Timothy et al. (2016) Prediction of Intravenous Busulfan Clearance by Endogenous Plasma Biomarkers Using Global Pharmacometabolomics. Metabolomics 12:|
|Mielcarek, Marco; Furlong, Terry; O'Donnell, Paul V et al. (2016) Posttransplantation cyclophosphamide for prevention of graft-versus-host disease after HLA-matched mobilized blood cell transplantation. Blood 127:1502-8|
|McCune, Jeannine S; Bemer, Meagan J (2016) Pharmacokinetics, Pharmacodynamics and Pharmacogenomics of Immunosuppressants in Allogeneic Haematopoietic Cell Transplantation: Part I. Clin Pharmacokinet 55:525-50|
|Scian, Michele; Guttman, Miklos; Bouldin, Samantha D et al. (2016) The Myeloablative Drug Busulfan Converts Cysteine to Dehydroalanine and Lanthionine in Redoxins. Biochemistry 55:4720-30|
|McCune, Jeannine S; Bemer, Meagan J; Long-Boyle, Janel (2016) Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics of Immunosuppressants in Allogeneic Hematopoietic Cell Transplantation: Part II. Clin Pharmacokinet 55:551-93|
|Navarro, Sandi L; Randolph, Timothy W; Shireman, Laura M et al. (2016) Pharmacometabonomic Prediction of Busulfan Clearance in Hematopoetic Cell Transplant Recipients. J Proteome Res 15:2802-11|
|McCune, J S; Jacobson, P; Wiseman, A et al. (2015) Optimizing drug therapy in pediatric SCT: focus on pharmacokinetics. Bone Marrow Transplant 50:165-72|
|Scian, Michele; Atkins, William M (2015) The busulfan metabolite EdAG irreversibly glutathionylates glutaredoxins. Arch Biochem Biophys 583:96-104|