Nonablative hematopoietic stem cell transplantation (HCT) with an unrelated donor graft has greatly expanded the number of patients suffering from hematologic diseases and malignancies who can be cured by HCT. However, current dosing methods for HCT regimens lead to substantial interpatient variability in the systemic exposure and commensurate percent donor T-cell chimerism. The parent grants have compelling data that percent donor chimerism is associated with the efficacy and toxicity of nonablative HCT. Our central hypothesis is the pharmacokinetic (PK) and drug-specific pharmacodynamics (PD) of fludarabine and mycophenolate mofetil (MMF), along with relevant metabolites, are biomarkers for donor chimerism. To test this hypothesis, we propose to develop population PK models and limited sampling schedules to characterize an individual patient's systemic exposure and to build popPK-PD models using PD endpoints specific for each drug's activity. We propose three specific aims to be tested in patients receiving fludarabine/total body irradiation conditioning, an unrelated peripheral blood mononuclear cell graft, and postgrafting immunosuppression of MMF and a calcineurin inhibitor.
In Aim 1, we will evaluate the PK and PD of plasma fludarabine and intracellular fludarabine triphosphate (FTP), its active metabolite. Using a novel analytical method, we are uniquely poised to measure in-vitro FTP formation by CD4+ and CD8+ cells obtained from patients awaiting HCT and evaluate the cellular mechanisms of FTP formation. We will evaluate fludarabine- specific PD, specifically evaluating the relationship of these PK endpoints with the decline in circulating CD4+ and CD8+ cells.
In Aim 2, we will characterize the PK and PD of MMF's active metabolite, mycophenolic acid (MPA), and to confirm our findings that a low MPA AUC increases the risk of low percent donor chimerism and rejection. We also propose to evaluate the genetic mechanisms of MPA clearance and to characterize the PD of MPA and inosine monophosphate dehydrogenase (IMPDH) activity, the enzyme inhibited by MPA.
In Aim 3, we propose to evaluate if percent donor T-cell chimerism is associated with the PK and drug-specific PD biomarkers of fludarabine and MMF. We propose to evaluate the PD of donor T-cell chimerism with the PK and drug-specific PD markers evaluated in Aims 1 and 2. Our individual areas of expertise, in combination with our history of collaborations, demonstrate that we are well-poised to test the central hypothesis, thus providing a unique opportunity for these ancillary studies to improve outcomes for patients with hematologic disease or malignancies receiving HCT. The goal of these studies is to identify patient-specific factors related to the balance between the recipient cells and donor cells in patients who receive a hematopoietic stem cell transplant. We will look at two types of patient-specific factors - how the patients'body breaks down and how their bodies immediately responds - to two drugs, fludarabine and mycophenolate.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL091744-04
Application #
7996579
Study Section
Special Emphasis Panel (ZHL1-CSR-H (O1))
Program Officer
Wagner, Elizabeth
Project Start
2008-03-01
Project End
2012-12-31
Budget Start
2011-01-01
Budget End
2012-12-31
Support Year
4
Fiscal Year
2011
Total Cost
$427,179
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
McCune, Jeannine S; Vicini, Paolo; Salinger, David H et al. (2015) Population pharmacokinetic/dynamic model of lymphosuppression after fludarabine administration. Cancer Chemother Pharmacol 75:67-75
McCune, Jeannine S; Mager, Donald E; Bemer, Meagan J et al. (2015) Association of fludarabine pharmacokinetic/dynamic biomarkers with donor chimerism in nonmyeloablative HCT recipients. Cancer Chemother Pharmacol 76:85-96
Li, Hong; Mager, Donald E; Sandmaier, Brenda M et al. (2014) Pharmacokinetic and pharmacodynamic analysis of inosine monophosphate dehydrogenase activity in hematopoietic cell transplantation recipients treated with mycophenolate mofetil. Biol Blood Marrow Transplant 20:1121-9
Bemer, Meagan J; Risler, Linda J; Phillips, Brian R et al. (2014) Recipient pretransplant inosine monophosphate dehydrogenase activity in nonmyeloablative hematopoietic cell transplantation. Biol Blood Marrow Transplant 20:1544-52
Jaklič, Alenka; Collins, Carol J; Mrhar, Aleš et al. (2013) High prevalence of potential drug interactions affecting mycophenolic acid pharmacokinetics in nonmyeloablative hematopoietic stem cell transplant recipients. Int J Clin Pharmacol Ther 51:711-7
Bemer, Meagan J; Sorror, Mohamed; Sandmaier, Brenda M et al. (2013) A pilot pharmacologic biomarker study in HLA-haploidentical hematopoietic cell transplant recipients. Cancer Chemother Pharmacol 72:607-18
McDermott, Cara L; Sandmaier, Brenda M; Storer, Barry et al. (2013) Nonrelapse mortality and mycophenolic acid exposure in nonmyeloablative hematopoietic cell transplantation. Biol Blood Marrow Transplant 19:1159-66
Li, H; Mager, D E; Sandmaier, B M et al. (2013) Population pharmacokinetics and dose optimization of mycophenolic acid in HCT recipients receiving oral mycophenolate mofetil. J Clin Pharmacol 53:393-402
Li, Hong; Mager, Donald E; Bemer, Meagan J et al. (2012) A limited sampling schedule to estimate mycophenolic Acid area under the concentration-time curve in hematopoietic cell transplantation recipients. J Clin Pharmacol 52:1654-64
Raccor, Brianne S; Claessens, Adam J; Dinh, Jean C et al. (2012) Potential contribution of cytochrome P450 2B6 to hepatic 4-hydroxycyclophosphamide formation in vitro and in vivo. Drug Metab Dispos 40:54-63

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