Population Pharmacokinetics of Clofarabine as Part of Pretransplantation Conditioning in Pediatric Subjects before Hematopoietic Cell Transplantation

Hechuan Wang, Aksana K. Jones, Christopher C. Dvorak, Liusheng Huang, Paul Orchard, Vijay Ivaturi, Janel Long-Boyle

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The primary objective of this work was to characterize the pharmacokinetics (PK) of systemic clofarabine (clo-fara) in pediatric allogeneic hematopoietic cell transplantation (HCT) recipients receiving either nucleoside monotherapy or a dual nucleoside analog preparative regimen. Fifty-one children (median age, 4.9 years; range,.25 to 14.9 years) undergoing allogeneic HCT for a variety of malignant and nonmalignant disorders underwent PK assessment. Plasma samples were collected over the 4 to 5 days of clo-fara treatment and quantified for clo-fara, using a validated liquid chromatography/tandem mass spectrometry assay. Nonlinear mixed-effects modeling was used to develop the population PK model, including identification of covariates that influenced drug disposition. In agreement with previously published models, a 2-compartment PK model with first-order elimination best described the PK of clo-fara. Final parameter estimates for clo-fara were consistent with previous reports and were as follows: clearance (CL), 23 L/h/15 kg; volume of the central compartment, 42 L/15 kg; volume of peripheral compartment, 47 L/15 kg; and intercompartmental CL, 9.8 L/h/15 kg. Unexplained variability was acceptable at 33%, and the additive residual error (reflective of the assay) was estimated to be 0.36 ng/mL. Patient-specific factors significantly impacting clo-fara CL included actual body weight and age. The covariate model was able to estimate clo-fara CL with good precision in children spanning a wide age range from infancy to early adulthood and demonstrates the need for variable dosing in children of different ages. For example, the dose required for a 6-month and 1-year old was approximately 43% and 17% lower, respectively, than the typical 40 mg/m2dose to achieve the median AUC0-24of 1.04 mg·h/L in the study population. Despite the known renal elimination of clo-fara, no significant clinical parameters for renal function were retained in the final model (P>.05). Coadministration of fludarabine with clo-fara did not alter the CL of clo-fara (P>.05). These results will help inform individualized dosing strategies for clo-fara to improve clinical outcomes and limit drug-related adverse events in children undergoing HCT.

Original languageEnglish (US)
Pages (from-to)1603-1610
Number of pages8
JournalBiology of Blood and Marrow Transplantation
Volume25
Issue number8
DOIs
StatePublished - Aug 2019

Keywords

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

PubMed: MeSH publication types

  • Clinical Trial
  • Journal Article
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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