Pharmacokinetics and Model-Based Dosing to Optimize Fludarabine Therapy in Pediatric Hematopoietic Cell Transplant Recipients

Vijay Ivaturi, Christopher C. Dvorak, Danna Chan, Tao Liu, Morton J. Cowan, Justin Wahlstrom, Melisa Stricherz, Cathryn Jennissen, Paul J. Orchard, Jakub Tolar, Sung Yun Pai, Liusheng Huang, Francesca Aweeka, Janel Long-Boyle

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

A prospective multicenter study was conducted to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of fludarabine plasma (f-ara-a) and intracellular triphosphate (f-ara-ATP) in children undergoing hematopoietic cell transplantation (HCT) and receiving fludarabine with conditioning. Plasma and peripheral blood mononuclear cells (PBMCs) were collected over the course of therapy for quantitation of f-ara-a and f-ara-ATP. Nonlinear mixed-effects modeling was used to develop the PK model, including identification of covariates impacting drug disposition. Data from a total of 133 children (median age, 5 years; range,.2 to 17.9) undergoing HCT for a variety of malignant and nonmalignant disorders were available for PK-PD modeling. The implementation of allometric scaling of PK parameters alone was insufficient to describe drug clearance, particularly in very young children. Renal impairment was predicted to increase drug exposure across all ages. The rate of f-ara-a entry into PBMCs (expressed in pmoles per million cells) decreased over the course of therapy, resulting in 78% lower f-ara-ATP after the fourth dose (1.7 pmoles/million cells [range,.2 to 7.2]) compared with first dose (7.9 pmoles/million cells [range,.7 to 18.2]). The overall incidence of treatment-related mortality (TRM) was low at 3% and 8% at days 60 and 360, respectively, and no association with f-ara-a exposure and TRM was found. In the setting of malignancy, disease-free survival was highest at 1 year after HCT in subjects achieving a systemic f-ara-a cumulative area under the curve (cAUC) greater than 15 mg*hour/L compared to patients with a cAUC less than 15 mg*hour/L (82.6% versus 52.8% P =.04). These results suggest that individualized model-based dosing of fludarabine in infants and young children may reduce morbidity and mortality through improved rates of disease-free survival and limiting drug-related toxicity. ClinicalTrials.gov Identifier: NCT01316549

Original languageEnglish (US)
Pages (from-to)1701-1713
Number of pages13
JournalBiology of Blood and Marrow Transplantation
Volume23
Issue number10
DOIs
StatePublished - Oct 2017

Bibliographical note

Funding Information:
Financial disclosure: This work was supported by an Early Career Award through the Thrasher Research Fund and the National Center for Advancing Translational Sciences , National Institutes of Health , through UCSF-CTSI Grant Number KL2 TR000143 (JLB). Funding from NIH Grant U54 AI 082973 supported MJC, CCD, and SYP. SYP was supported by the National Heart, Lung, and Blood Institute (NHLBI) Gene Therapy Resource Program (GTRP) contract HHSM2682012000021 . Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

Publisher Copyright:
© 2017 The American Society for Blood and Marrow Transplantation

Keywords

  • Allogeneic
  • Fludarabine
  • Hematopoietic cell transplantation
  • Pediatric
  • Pharmacodynamics
  • Pharmacokinetics

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