Association of fludarabine pharmacokinetic/dynamic biomarkers with donor chimerism in nonmyeloablative HCT recipients

作者：McCune Jeannine S^*; Mager Donald E; Bemer Meagan J; Sandmaier Brenda M; Storer Barry E; Heimfeld Shelly

来源：Cancer Chemotherapy and Pharmacology, 2015, 76(1): 85-96.

DOI：10.1007/s00280-015-2768-x

• Fludarabine
• Biomarkers
• Nucleoside analogs
• Pharmacokinetics
• Pharmacodynamics
• Hematopoietic cell transplantation

Fludarabine monophosphate (fludarabine) is an integral component of many reduced-intensity conditioning regimens for hematopoietic cell transplantation (HCT). Fludarabine's metabolite, 9-beta-D-arabinofuranosyl-2-fluoroadenine (F-ara-A), undergoes cellular uptake and activation to form the active cytotoxic metabolite fludarabine triphosphate (F-ara-ATP), which inhibits cellular DNA synthesis in CD4(+) and CD8(+) cells. In this study, we evaluated whether fludarabine-based pharmacologic biomarkers were associated with clinical outcomes in HCT recipients.
Participants with hematologic diseases were conditioned with fludarabine and low-dose total body irradiation (TBI) followed by allogeneic HCT and post-grafting immunosuppression. After fludarabine administration, we evaluated pharmacological biomarkers for fludarabine-F-ara-A area under the curve (AUC) and the ratio of circulating CD4(+) and CD8(+) cells (CD4(+)/CD8(+) ratio) after fludarabine administration-in 102 patients; F-ara-ATP accumulation rate in enriched CD4(+) and CD8(+) cells was evaluated in 36 and 34 patients, respectively.
Interpatient variability in the pharmacological biomarkers was high, ranging from 3.7-fold (F-ara-A AUC) to 39-fold (F-ara-ATP in CD8(+) cells). Circulating CD8(+) cells were more sensitive to fludarabine administration. A population pharmacokinetic-based sampling schedule successfully allowed for estimation of F-ara-A AUC in this outpatient population. There was a poor correlation between the F-ara-AUC and the F-ara-ATP accumulation rate in CD4(+) (R (2) = 0.01) and CD8(+) cells (R (2) = 0.00). No associations were seen between the four biomarkers and clinical outcomes (day +28 donor T cell chimerism, acute graft-versus-host disease (GVHD), neutrophil nadirs, cytomegalovirus reactivation, chronic GVHD, relapse, non-relapse mortality, or overall mortality).
Considerable interpatient variability exists in pharmacokinetic and fludarabine-based biomarkers, but these biomarkers are not associated with clinical outcomes in fludarabine/TBI-conditioned patients.

• 出版日期2015-7