Population pharmacokinetics of intravenous Erwinia asparaginase in pediatric acute lymphoblastic leukemia patients
Sebastiaan D.T. Sassen,
Ron A.A. Mathôt,
Rob Pieters,
Robin Q.H. Kloos,
Valérie de Haas,
Gertjan J.L. Kaspers,
Cor van den Bos,
Wim J.E. Tissing,
Maroeska te Loo,
Marc B. Bierings,
Wouter J.W. Kollen,
Christian M. Zwaan,
Inge M. van der Sluis
Affiliations
Sebastiaan D.T. Sassen
Department of Pediatric Oncology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, the Netherlands
Ron A.A. Mathôt
Department of Hospital Pharmacy, Academic Medical Center, University of Amsterdam, the Netherlands
Rob Pieters
Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
Robin Q.H. Kloos
Department of Pediatric Oncology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, the Netherlands
Valérie de Haas
Dutch Childhood Oncology Group, The Hague, the Netherlands
Gertjan J.L. Kaspers
Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands;Department of Pediatric Oncology, VU University Medical Center, Amsterdam, the Netherlands
Cor van den Bos
Department of Pediatric Oncology, Emma Children’s Hospital, Academic Medical Center, Amsterdam, the Netherlands
Wim J.E. Tissing
Department of Pediatric Oncology, Beatrix Children’s Hospital, University Medical Center, Groningen, the Netherlands
Maroeska te Loo
Department of Pediatric Hemato-Oncology, Radboud University Nijmegen Medical Center, the Netherlands
Marc B. Bierings
Pediatric Blood and Marrow Transplantation Program, University Medical Center Utrecht/Wilhelmina Children’s Hospital, the Netherlands
Wouter J.W. Kollen
Department of Pediatric Immunology, Hemato-Oncology and Stem Cell Transplantation, Leiden University Medical Center, the Netherlands
Christian M. Zwaan
Department of Pediatric Oncology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, the Netherlands
Inge M. van der Sluis
Department of Pediatric Oncology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, the Netherlands
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
