Population pharmacokinetics of clofarabine for allogeneic hematopoietic cell transplantation in paediatric patients

Abstract

Aims: Clofarabine has recently been evaluated as part of the conditioning regimen for allogeneic hematopoietic stem cell transplantation (HCT) in children. Pharmacokinetic (PK) exposure of different agents commonly used in conditioning regimens is strongly related to HCT outcome. Consequently, the PK of clofarabine may be important for outcome. This report describes the population PK of clofarabine in paediatric patients and one adult.

Methods: From 80 paediatric (0.5-18 years) and 1 adult patient (37 years), 805 plasma concentrations were included in pharmacokinetic analyses using nonlinear mixed effects modelling.

Results: A two-compartment model adequately described the PK of clofarabine. Body weight and estimated glomerular filtration rate (eGFR) were included as covariates. Clearance was differentiated into nonrenal and renal clearance (approximately 55% of total clearance), resulting in population estimates of 24.0 L/h (95% confidence interval [CI] 13.7-34.4) and 29.8 L/h (95% CI 23.9-36.1) for a patient of 70 kg with normal renal function, respectively. Unexplained interindividual variability in clearance was 17.8% (95% CI 14.6-22.4). A high variability in exposure was observed (range area under the curve_T0-inf 1.8-6.0 mg/L*h) after body surface area (BSA) based dosing. Interestingly, children with low body weight had a lower exposure than children with a higher body weight, which indicates that the currently practised BSA-based dosing is not adequate for clofarabine.

Conclusion: A clofarabine dosing algorithm based on this PK model, using body weight and eGFR, results in a more predictable exposure than BSA-based dosing. However, the exact target exposure needs to be further investigated.

Keywords: allogeneic hematopoietic cell transplantation; clinical pharmacology; clofarabine; paediatrics; pharmacokinetics.

FIGURE 1

Clofarabine plasma concentrations vs time after dose. Each line corresponds to a single dose

FIGURE 2

Exposure variability after dosing in the trial (A, B, C) and after dosing with suggested dosing algorithm (D, E, F). (A) Histogram (grey area) and density plot (black solid line) of the observed AUC_T0–inf. (B) Boxplots of the observed AUC_T0–inf per body weight quartile. (C) Boxplots of the observed AUC_T0–inf per renal function category. (D) Histogram (grey area) and density plot (black solid line) of the calculated AUC_T0–inf. (E) Boxplots of the calculated AUC_T0–inf per body weight quartile. (F) Boxplots of the calculated AUC_T0–inf per renal function category

FIGURE 3

Body weight stratified prediction‐corrected visual predictive check. Black lines depict the observed median (solid) and 2.5% and 97.5% percentile (dashed) concentrations. Dark‐ and light‐grey areas represent 95% prediction intervals of the simulated mean and the 2.5 and 97.5% percentiles, respectively. Round dots represent observations

FIGURE 4

Line plot of the 4‐day cumulative clofarabine dose as a function of the body weight (kg) for several relative renal function values (RF)