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

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.

Keywords: Allogeneic; Fludarabine; Hematopoietic cell transplantation; Pediatric; Pharmacodynamics; Pharmacokinetics.

Conflict of interest statement

Conflict of interest statement: There are no conflicts of interest to report.

Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.

Individual fit plots of observed and predicted time concentration data of (A) f-ara-a and (B) f-ara-ATP for several representative patients. Open circles represent the observed concentrations, black solid line is the population prediction, and the dashed line is the individual prediction.

Figure 2.

Model-predicted dose of fludarabine in mg/kg aimed to achieve an daily AUC target of 4.5 mg*hour/L for (A) ages .2 to 20 years of age with varying degrees of renal function and (B) ages 0 to 2 years of age with varying degrees of renal function.

Figure 3.

OS for all subjects at 1 year after HCT. (A) Shows the proportion of patients surviving plotted by observed f-ara- cAUC quartile and regardless of diagnosis. (B) displays the OS stratified by malignant or nonmalignant diagnosis.

Figure 4.

OS at 1 year after HCT for patients with a nonmalignant diagnosis presented by f-ara-a cAUC quartiles.

Figure 5.

DFS in patients with malignant disease only at 1 year after HCT. (A) Shows box plots of the proportion of patients with DFS by observed f-ara- cAUC quartiles. (B) Displays survival curves for the proportion of patients with DFS stratified by f-ara-a cAUC quartiles of observed data.