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

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 AUC_0-24of 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.

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

FIGURE 1.

Scatterplot of dose-normalized (by 10 mg/m²) plasma clo-fara concentration-time profiles. Black points represent the observed dose-normalized clo-fara concentrations from the different dose regimens: 10mg/m²(open circles), 30mg/m²(open triangles) and 40mg/m²(open squares). The black solid line represents the median values of the observed concentrations.

FIGURE 2.

(A) Observed vs. individual-predicted clo-fara plasma concentrations. (B) Observed vs. population-predicted clo-fara plasma concentrations. (C) Normalized prediction distribution error vs. time after first dose. (D) Normalized prediction distribution error vs. population predicted clo-fara plasma concentrations.

FIGURE 3.

Representative individual fit plots of observed and predicted time-concentration data of for the different dosing regimens: 10mg/m²(top row), 30mg/m²(middle row) and 40mg/m²(bottom row). Open circles represent the observed concentrations, black solid line is the population prediction, and the dashed line is individual prediction.

FIGURE 4.

Model-predicted dose of clofarabine in mg/kg aimed to achieve a daily AUC_0–24 of 1.04mg•hr/L for (A) 0–20 years of age and (B) 0–2 years of age. The dashed line in plot (A) represents the doses at corresponding ages based on the conventional dose 40mg/m². The dashed line in plot (B) represents the modified regimen of 1.33 kg in young children.