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

摘要

Purpose: 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.