Prospective Validation and Refinement of a Population Pharmacokinetic Model of Fludarabine in Children and Young Adults Undergoing Hematopoietic Cell Transplantation

Abstract

Fludarabine is a nucleoside analog with antileukemic and immunosuppressive activity commonly used in allogeneic hematopoietic cell transplantation (HCT). Several fludarabine population pharmacokinetic (popPK) and pharmacodynamic models have been published enabling the movement towards precision dosing of fludarabine in pediatric HCT; however, developed models have not been validated in a prospective cohort of patients. In this multicenter pharmacokinetic study, fludarabine plasma concentrations were collected via a sparse-sampling strategy. A fludarabine popPK model was evaluated and refined using standard nonlinear mixed effects modelling techniques. The previously described fludarabine popPK model well-predicted the prospective fludarabine plasma concentrations. Individuals who received model-based dosing (MBD) of fludarabine achieved significantly more precise overall exposure of fludarabine. The fludarabine popPK model was further improved by both the inclusion of fat-free mass instead of total body weight and a maturation function on fludarabine clearance. The refined popPK model is expected to improve dosing recommendations for children younger than 2 years and patients with higher body mass index. Given the consistency of fludarabine clearance and exposure across its multiple days of administration, therapeutic drug monitoring is not likely to improve targeted exposure attainment.

Good engraftment after reduced intensity targeted busulfan‐based conditioning and matched related donor hematopoietic cell transplantation in hemoglobinopathies

“…However, fludarabine‐associated neurotoxicity is a rare but dose‐dependent complication. Furthermore, there is growing evidence that 4‐day fludarabine regimen should be sufficient 44,45 . Our RIC protocol uses a targeted approach to sub‐myeloablative busulfan dosing that allows for dose optimization based on individual patient pharmacokinetics through multiple serum level monitoring and post‐dose adjustment, with the option to omit or add busulfan doses 46 .…”

“…Furthermore, there is growing evidence that 4-day fludarabine regimen should be sufficient. 44,45 Our RIC protocol uses a targeted approach to sub-myeloablative busulfan dosing that allows for dose optimization based on individual patient pharmacokinetics through multiple serum level monitoring and post-dose adjustment, with the option to omit or add busulfan doses. 46 This approach obviates the need for TBI or additional alkylators like thiotepa, thereby mitigating not only acute toxicity, that is, mucositis but also minimizing the risk of late effects after TBI.…”