Personalized fludarabine dosing to reduce nonrelapse mortality in hematopoietic stem-cell transplant recipients receiving reduced intensity conditioning.
Patients undergoing hematopoietic cell transplantation (HCT) with reduced intensity conditioning (RIC) commonly receive fludarabine. Higher exposure of F-ara-A, the active component of fludarabine, has been associated with a greater risk of nonrelapse mortality (NRM). We sought to develop a model for fludarabine dosing in adult HCT recipients that would allow for precise dose targeting and predict adverse clinical outcomes. We developed a pharmacokinetic model from 87 adults undergoing allogeneic RIC HCT that predicts F-ara-A population clearance (Clpop) accounting for ideal body weight and renal function. We then applied the developed model to an independent cohort of 240 patients to identify whether model predictions were associated with NRM and acute graft versus host disease (GVHD). Renal mechanisms accounted for 35.6% of total F-ara-A Clpop. In the independent cohort, the hazard ratio of NRM at day 100 was significantly higher in patients with predicted F-ara-A clearance (Clpred) <8.50 L/h (P < 0.01) and area under the curve (AUCpred) >6.00 μg × h/mL (P = 0.01). A lower Clpred was also associated with more NRM at month 6 (P = 0.01) and trended toward significance at 12 months (P = 0.05). In multivariate analysis, low fludarabine clearance trended toward higher risk of acute GVHD (P = 0.05). We developed a model that predicts an individual's systemic F-ara-A exposure accounting for kidney function and weight. This model may provide guidance in dosing especially in overweight individuals and those with altered kidney function.
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minn.
Kinjal
K
Sanghavi
Department of Internal Medicine, Baylor College of Medicine, Houston, Tex.
Anthony
A
Wiseman
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minn.
Mark N
MN
Kirstein
Biostatistics & Informatics Core, Masonic Cancer Center, University of Minnesota, Minneapolis, Minn.
Qing
Q
Cao
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minn.
Richard
R
Brundage
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minn.
Kyle
K
Jensen
University of Minnesota Medical Center, Minneapolis, Minn.
John
J
Rogosheske
University of Minnesota Medical Center, Minneapolis, Minn.
Andy
A
Kurtzweil
Department of Clinical Pharmacy, School of Pharmacy, University of California, San Francisco, Calif.
Janel
J
Long-Boyle
Department of Pediatric Bone Marrow Transplantation, University of Minnesota, Minneapolis, Minn.
John
J
Wagner
Department of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minn.
Erica D
ED
Warlick
Department of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minn.
Claudio G
CG
Brunstein
Department of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minn.
Daniel J
DJ
Weisdorf
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minn. Electronic address: jacob117@umn.edu.
Pamala A
PA
Jacobson
D000328:Adult; D000368:Aged; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000401:mortality*; D006801:Humans; D008297:Male; D008875:Middle Aged; D057285:Precision Medicine; D012008:Recurrence; D012044:Regression Analysis; D019172:Transplantation Conditioning / Q000401:mortality*; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult
D014740:Vidarabine; C024352:fludarabine