Pharmacokinetics of fludarabine and its association with clinical outcomes in paediatric haematopoietic stem cell transplantation patients

Bone Marrow Transplant. 2019 Feb;54(2):284-292. doi: 10.1038/s41409-018-0260-z. Epub 2018 Jun 18.

Abstract

Fludarabine is used as a common component of conditioning regimens for haematopoietic stem cell transplantation (HSCT). However, knowledge regarding the pharmacokinetic characteristics of once-daily fludarabine dosing in children is limited. This study investigated the pharmacokinetics of fludarabine and evaluated its associations with clinical outcomes in paediatric patients. A total of 802 blood samples obtained from 43 paediatric patients who underwent HSCT were included in a population pharmacokinetic analysis using non-linear mixed-effects modelling. The relationships between systemic 9-β-d-arabinofuranosyl-2-fluoroadenine (F-ara-A) exposure derived from the model and the clinical outcome variables were explored. A two-compartment model with proportional residual error adequately described the pharmacokinetics of F-ara-A. The body surface area and glomerular filtration rate were significant covariates for the clearance of F-ara-A. After the first dose of fludarabine at 40 mg/m2, the median (min-max) values for the area under the concentration-time curve (AUC) from dosing to infinity and the elimination half-life were 4696 (3056-10,477) ng·h/mL and 7.95 (4.78-10.88) h, respectively. No significant associations were found between systemic exposure and graft-vs.-host disease, neurologic and pulmonary complications, relapse or survival. Systemic exposure was comparable to that of previous reports from different populations and had no association with clinical outcomes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Area Under Curve
  • Body Surface Area
  • Child
  • Child, Preschool
  • Female
  • Glomerular Filtration Rate
  • Hematopoietic Stem Cell Transplantation / methods*
  • Hematopoietic Stem Cell Transplantation / mortality
  • Humans
  • Infant
  • Male
  • Nonlinear Dynamics*
  • Pediatrics
  • Republic of Korea
  • Transplantation Conditioning / methods*
  • Treatment Outcome
  • Vidarabine / administration & dosage
  • Vidarabine / analogs & derivatives*
  • Vidarabine / pharmacokinetics
  • Vidarabine / pharmacology

Substances

  • Vidarabine
  • fludarabine