title: Comparative pharmacokinetic/pharmacodynamic characterisation of a new pegylated recombinant E. coli L-asparaginase preparation (MC0609) in Beagle dog.
abstract: OBJECTIVE
  A new pegylated recombinant L-asparaginase (MC0609) was designed to improve pharmacokinetic characteristics and to further reduce immunogenicity in comparison with the currently marketed pegylated Escherichia coli L-asparaginase (pegaspargase, Oncaspar(®)).
  
  
  METHODS
  Comparative pharmacokinetics (PK), bioavailability, pharmacodynamics and immunogenicity studies were performed in CD(®) rats and Beagle dogs after intravenous (i.v.) and intramuscular (i.m.) single-dose administration of MC0609 or Oncaspar(®). Bioanalytical data on enzymatic activity in serum of animals were used to develop a population pharmacokinetic (PopPK) model to simulate different dosages of MC0609 comparable to the activity time profile of Oncaspar(®).
  
  
  RESULTS
  In contrast to Oncaspar(®), which showed an accelerated elimination over time, a constant serum elimination of enzymatic activity over time was seen for MC0609. Linear PK of MC0609 resulted in a prolonged and dose-dependent duration of enzymatic activity and longer depletion of L-asparagine in peripheral blood. The different PK characteristics of MC0609 and Oncaspar(®) were confirmed by PopPK analysis and model development. The PK parameters of Oncaspar(®) in dog scaled to body surface area were in the same range than the parameters determined in paediatric acute lymphoblastic leukaemia patients. Therefore, the dog is considered a clinically relevant model for PK evaluation of Oncaspar(®). Distinct differences in immunogenic potential of both preparations were detected after single-dose administration of a therapeutic dose to dogs. An absolute bioavailability of 66 % was calculated for the intramuscular administration of MC0609.
  
  
  CONCLUSIONS
  The new pegylated recombinant L-asparaginase preparation MC0609 revealed striking differences in PK/PD properties compared with Oncaspar(®) in rat and dog.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Klinische Pharmazie, Westfälische Wilhelms-Universität Münster, Raum A 120.210, Corrensstraße 48, 48149, Münster, Germany, stephan-borghorst@gmx.de.
authors.forename: Stephan
authors.initials: S
authors.lastname: Borghorst
authors.forename: Georg
authors.initials: G
authors.lastname: Hempel
authors.forename: Sabine
authors.initials: S
authors.lastname: Poppenborg
authors.forename: Dieter
authors.initials: D
authors.lastname: Franke
authors.forename: Thorsten
authors.initials: T
authors.lastname: König
authors.forename: Joachim
authors.initials: J
authors.lastname: Baumgart
mesh_terms: D000818:Animals; D001215:Asparaginase / Q000097:blood* / Q000493:pharmacokinetics*; D001682:Biological Availability; D004285:Dogs; D004926:Escherichia coli / Q000201:enzymology*; D005260:Female; D006801:Humans; D008297:Male; D011092:Polyethylene Glycols / Q000493:pharmacokinetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy*; D051381:Rats; D011994:Recombinant Proteins / Q000097:blood* / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C042705:pegaspargase; D001215:Asparaginase