Comparative pharmacokinetic/pharmacodynamic characterisation of a new pegylated recombinant E. coli l-asparaginase preparation (MC0609) in Beagle dog

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.