Lipidomics of cyclophosphamide 4‐hydroxylation in patients receiving post‐transplant cyclophosphamide |
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| Authors: | Sandi L. Navarro Zihan Zheng Timothy W. Randolph Ryotaro Nakamura Brenda M. Sandmaier David Hockenbery Jeannine S. McCune |
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| Affiliation: | 1. Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle Washington, USA ; 2. Clinical Research Division, Fred Hutchinson Cancer Center, Seattle Washington, USA ; 3. Department of Hematologic Malignancies Translational Sciences, City of Hope, Duarte California, USA ; 4. Department of Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte California, USA ; 5. Department of Medicine, University of Washington, Seattle Washington, USA |
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| Abstract: | Biomarker‐guided dosing may improve the efficacy and toxicity of cyclophosphamide (CY); however, clinical studies evaluating their association with the area under the plasma concentration–time curve (AUC) of CY and its metabolites are time‐ and resource‐intensive. Therefore, we sought to identify lipidomic biomarkers associated with the time‐varying differences in CY formation clearance to 4‐hydroxycyclophosphamide (4HCY), the principal precursor to CY''s cytotoxic metabolite. Hematopoietic cell transplant (HCT) patients receiving post‐transplant CY (PT‐CY) were enrolled, cohort 1 (n = 25) and cohort 2 (n = 26) donating longitudinal blood samples before they started HCT (pre‐HCT), before infusion of the donor allograft (pre‐graft), before the first dose of PT‐CY (pre‐CY) and 24 h after the first dose of PT‐CY (24‐h post‐CY) which is also immediately before the second dose of CY. A total of 409 and 387 lipids were quantitated in the two cohorts, respectively. Associations between lipids, individually and at a class level, and the ratio of 4HCY/CY AUC (i.e., 4HCY formation clearance) were evaluated using linear regression with a false discovery rate <0.05. There were no individual lipids that passed control for false discovery at any time point. These results demonstrate the feasibility of lipidomics, but future studies in larger samples with multiple omic tools are warranted to optimize CY dosing in HCT. Study Highlights - WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
The old yet commonly used drug cyclophosphamide (CY) has a complex pharmacokinetic disposition. There is a paucity of information regarding the formation clearance of 4‐hydroxycyclophosphamide (4HCY), the precursor to CY’s primary cytotoxic metabolite phosphoramide mustard. To date, scientists have not been able to create a more effective or safer analog to CY or to identify a precision medicine tool consistently associated with the efficacy, toxicity, or pharmacokinetics of CY. - WHAT QUESTION DID THIS STUDY ADDRESS?
This study addresses the question if the plasma lipidome before post‐transplant cyclophosphamide (PT‐CY) administration in hematopoietic cell transplant (HCT) patients is associated with the ratio of 4HCY/CY area under the plasma concentration–time curve (AUC). - WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
This study shows that longitudinal collection of plasma lipidomic samples is feasible in HCT patients receiving PT‐CY. However, in this small patient population, we could not find an association of the plasma lipidome with the ratio of 4HCY/CY AUC. Furthermore, this study shows that the plasma lipidome changes over the ~21‐day period that starts before HCT to 24‐h after the first PT‐CY dose. This study is also among the first to evaluate the plasma lipidome in HCT patients. - HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
This study shows how interrogating the plasma lipidome may provide insight into the pharmacokinetics of CY and how interrogating the plasma lipidome is feasible for biomarker studies. |
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