title: Population Pharmacokinetics to Model the Time-Varying Clearance of the PEGylated Asparaginase Oncaspar®in Children with Acute Lymphoblastic Leukemia.
abstract: The pharmacokinetics of the polyethylene glycol (PEG)-conjugated asparaginase Oncaspar®are characterized by an increase in elimination over time. The focus of our analysis is the better understanding of this time-dependency.
  
  
  
  In paediatric acute lymphoblastic leukemia therapy (AIEOP-BFM ALL 2009), two administrations of Oncaspar®(2500 U/m2intravenously) in induction phase (14-day interval) and one single administration in reinduction were followed by weekly monitoring of asparaginase activity. Non-linear mixed-effects modeling techniques (NONMEM) were used. Samples indicating immunological inactivation were excluded to describe the pharmacokinetics under standard conditions. Models with time-constant or time-varying clearance (CL) as well as transit compartment models with an increase in CL over a chain of compartments were investigated.
  
  
  
  Models with time-constant elimination could not adequately describe 6107 asparaginase activities from 1342 patients. Implementing a time-varying CL improved the fit. Modeling an increase of CL over time after dose (Emax- and Weibull-functions) were superior to models with an increase of CL over time after the first administration. However, a transit compartment model came out to be the best structural model.
  
  
  
  The increase in elimination of PEGylated asparaginase appears to be driven by physicochemical processes that are drug-related. The observed hydrolytically in vitro instability of the drug leads to the hypothesis that this increase in CL might be due to an in vivo hydrolysis of the instable ester bond between PEG and the enzyme combined with an increased elimination of the partly de-PEGylated enzyme (Trial registered at www.clinicaltrials.gov , NCT0111744).
authors.affiliation: Paediatric Haematology and Oncology, University Hospital Muenster, Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Würthwein
authors.affiliation: Paediatric Haematology and Oncology, University Hospital Muenster, Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Lanvers-Kaminsky
authors.affiliation: Department of Pharmaceutical and Medical Chemistry-Clinical Pharmacy, Corrensstraße 48, 48149, Muenster, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Hempel
authors.affiliation: Department of Pharmaceutical and Medical Chemistry-Clinical Pharmacy, Corrensstraße 48, 48149, Muenster, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Gastine
authors.affiliation: Department of Pediatrics, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Schwanenweg 20, 24105, Kiel, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Möricke
authors.affiliation: Department of Pediatrics, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Schwanenweg 20, 24105, Kiel, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, P.O. Box 591, 75124, Uppsala, Sweden.
authors.forename: Mats O
authors.initials: MO
authors.lastname: Karlsson
authors.affiliation: Paediatric Haematology and Oncology, University Hospital Muenster, Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany. boosj@uni-muenster.de.
authors.forename: Joachim
authors.identifier: 0000-0003-2954-2025
authors.initials: J
authors.lastname: Boos
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; D017711:Nonlinear Dynamics; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D011092:Polyethylene Glycols; C042705:pegaspargase; D001215:Asparaginase