Comparative pharmacokinetic/pharmacodynamic characterisation of a new pegylated recombinant E. coli L-asparaginase preparation (MC0609) in Beagle dog
| Autor: | Georg Hempel, Joachim Baumgart, Sabine Poppenborg, Dieter Franke, Thorsten König, Stephan Borghorst |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Cancer Research Population Biological Availability Pharmacology Toxicology Beagle Polyethylene Glycols Therapeutic index Dogs Pharmacokinetics medicine Escherichia coli Animals Asparaginase Humans Pharmacology (medical) Tissue Distribution education Pegaspargase education.field_of_study Chemistry Immunogenicity Precursor Cell Lymphoblastic Leukemia-Lymphoma Recombinant Proteins Bioavailability Rats Oncology Pharmacodynamics Female medicine.drug |
| Zdroj: | Cancer chemotherapy and pharmacology. 74(2) |
| ISSN: | 1432-0843 |
| Popis: | 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®). 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®. 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. The new pegylated recombinant l-asparaginase preparation MC0609 revealed striking differences in PK/PD properties compared with Oncaspar® in rat and dog. |
| Databáze: | OpenAIRE |
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