Population pharmacokinetics of intravenous Erwinia asparaginase in pediatric acute lymphoblastic leukemia patients

Abstract

Erwinia asparaginase is an important component in the treatment of pediatric acute lymphoblastic leukemia. A large variability in serum concentrations has been observed after intravenous Erwinia asparaginase. Currently, Dutch Childhood Oncology Group protocols dose alterations are based on trough concentrations to ensure adequate asparaginase activity (≥100 IU/L). The aim of this study was to describe the population pharmacokinetics of intravenous Erwinia asparaginase to quantify and gather insight into inter-individual and inter-occasion variability. The starting dose was evaluated on the basis of the derived population pharmacokinetic parameters. In a multicenter prospective observational study, a total of 714 blood samples were collected from 51 children (age 1-17 years) with acute lymphoblastic leukemia. The starting dose was 20,000 IU/m² three times a week and adjusted according to trough levels from week three onwards. A population pharmacokinetic model was developed using NONMEM^® A 2-compartment linear model with allometric scaling best described the data. Inter-individual and inter-occasion variability of clearance were 33% and 13%, respectively. Clearance in the first month of treatment was 14% higher (P<0.01). Monte Carlo simulations with our pharmacokinetic model demonstrated that patients with a low weight might require higher doses to achieve similar concentrations compared to patients with high weight. The current starting dose of 20,000 IU/m² might result in inadequate concentrations, especially for smaller, lower weight patients, hence dose adjustments based on individual clearance are recommended. The protocols were approved by the institutional review boards. (Registered at NTR 3379 Dutch Trial Register; www.trialregister.nl).

Figure 1.

Asparaginase concentration (IU/L) versus time after dose in hours (h) for all patients and all occasions on a semi-log plot. This shows the large inter-patient variability in plasma concentrations as collected throughout treatment. Triangles (black) show concentrations prior to possible dose adjustments (first 2 weeks) and circles (blue) show observed concentrations with possible dose adjustments [therapeutic drug monitoring (TDM) after week two].

Figure 2.

Goodness-of-fit plots final model. (Upper left) Predicted population concentrations versus observed concentrations of the final model. (Upper right) Predicted individual concentrations versus observed concentrations of the final model. (Lower left) Individual weighted residuals versus individual predictions, (lower right) conditional weighted residuals versus time after dose. h: time in hours; IWRES: individual weighted residual predictions.

Figure 3.

Visual predictive check. Prediction corrected (Pred Corr) visual prediction plot of observed log asparaginase concentrations versus time after last Erwinia asparaginase dose in hours (h) of the final model. Red solid line shows the median observed concentrations and the surrounding opaque red area the simulation based 95% interval for the median. Red dashed lines indicate the observed 5% and 95% percentiles; surrounding opaque blue areas show the simulated 95% confidence intervals for the corresponding predicted percentiles.

Figure 4.

Simulated Erwinia asparaginase concentrations for a 10 kg and a 100 kg patient. Median and the 25% and 75% percentiles of the patients who achieve asparaginase concentrations (y-axis) after 48 hours for different Erwinia asparaginase doses (x-axis). (A) Concentrations for a 10 kg patient and (B) a 100 kg patient. Red dashed line is the target trough concentration of 100 IU/L.

Figure 5.

Erwinia asparaginase starting dose versus patient weight to achieve 100 IU/L or more after 48 hours (h). (A) Required starting dose in IU/kg and (B) IU/m² versus weight of patients in kilograms (kg) to achieve 100 IU/L or more after 48 h. Median (solid line), 25% and 75% percentiles (dashed line) and 10% and 90% percentiles (dotted line) of the patients with asparaginase concentrations of 100 IU/L or more with different weight (x-axis) and different starting doses (y-axis).

Figure 6.

Erwinia asparaginase starting dose versus patient body surface area to achieve 50 IU/L or more after 48 hours (h). (A) Required starting dose in IU/kg and (B) IU/m² versus weight of patients in kilograms (kg) to achieve 50 IU/L or more after 48 h. The median (solid line), 25% and 75% percentiles (dashed line) and 10% and 90% percentiles (dotted line) of the patients with asparaginase concentrations of 50 IU/L or more with different weight (x-axis) and different starting doses (y-axis).