title: 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/m2three 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/m2might 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).
authors.affiliation: Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.
authors.forename: Sebastiaan D T
authors.initials: SD
authors.lastname: Sassen
authors.affiliation: Department of Hospital Pharmacy, Academic Medical Center, University of Amsterdam, the Netherlands.
authors.forename: Ron A A
authors.initials: RA
authors.lastname: Mathôt
authors.affiliation: Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
authors.affiliation: Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.
authors.forename: Robin Q H
authors.initials: RQ
authors.lastname: Kloos
authors.affiliation: Dutch Childhood Oncology Group, The Hague, the Netherlands.
authors.forename: Valérie
authors.initials: V
authors.lastname: de Haas
authors.affiliation: Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.|Department of Pediatric Oncology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Gertjan J L
authors.initials: GJ
authors.lastname: Kaspers
authors.affiliation: Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Cor
authors.initials: C
authors.lastname: van den Bos
authors.affiliation: Department of Pediatric Oncology, Beatrix Children's Hospital, University Medical Center, Groningen, the Netherlands.
authors.forename: Wim J E
authors.initials: WJ
authors.lastname: Tissing
authors.affiliation: Department of Pediatric Hemato-Oncology, Radboud University Nijmegen Medical Center, the Netherlands.
authors.forename: Maroeska
authors.initials: M
authors.lastname: Te Loo
authors.affiliation: Pediatric Blood and Marrow Transplantation Program, University Medical Center Utrecht/Wilhelmina Children's Hospital, the Netherlands.
authors.forename: Marc B
authors.initials: MB
authors.lastname: Bierings
authors.affiliation: Department of Pediatric Immunology, Hemato-Oncology and Stem Cell Transplantation, Leiden University Medical Center, the Netherlands.
authors.forename: Wouter J W
authors.initials: WJ
authors.lastname: Kollen
authors.affiliation: Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Zwaan
authors.affiliation: Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands i.vandersluis@erasmusmc.nl.
authors.forename: Inge M
authors.initials: IM
authors.lastname: van der Sluis
mesh_terms: D061605:Administration, Intravenous; D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001215:Asparaginase / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D015233:Models, Statistical; D011159:Population Surveillance; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D015203:Reproducibility of Results
chemical_list: D000970:Antineoplastic Agents; D001215:Asparaginase