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Abstract
The main aim of this analysis was to characterize the population pharmacokinetics of native Escherichia coli asparaginase (ASNase medac™) in pediatric patients with previously untreated acute lymphoblastic leukemia. Secondary objective was to give further evidence for bioequivalence between ASNase medac™ and a new recombinant ASNase preparation. The authors reanalyzed 233 plasma samples from 16 children treated according to the DCOG-ALL 10 protocol (5000 U/m2 ASNase medac™) using NONMEM. Subsequently, assessment of bioequivalence was performed by including the preparation as a categorical covariate into the PopPK model when analyzing data of both preparations (480 samples, 32 children). A linear 2-compartment model with first-order elimination sufficiently described ASNase medac™ pharmacokinetics. The parameters found were as follows: total body clearance 0.13 L/h ± 12.4% per 1.73 m2, volume of distribution in the central compartment 4.11 L ± 12.3% per 70 kg, volume of distribution in the peripheral compartment 1.63 L per 70 kg and intercompartmental clearance 0.106 L/h (mean ± interindividual variability). A visual predictive check procedure and simulation of different dosages ASNase medac™ administered in the ALL-BFM protocol indicated adequate model performance. Assessment of bioequivalence provided a difference of about 14% in clearance of both preparations being too small to be considered as clinically relevant. A population pharmacokinetic model of ASNase medac™ in pediatric patients with previously untreated acute lymphoblastic leukemia was established. The model was able to describe asparaginase activity of different dosages in the ALL-BFM protocol and provides further evidence for bioequivalence between ASNase medac™ and a new recombinant asparaginase preparation.