Comparative pharmacokinetic/pharmacodynamic characterisation of a new pegylated recombinant E. coli L-asparaginase preparation (MC0609) in Beagle dog.
Cancer Chemother Pharmacol
; 74(2): 367-78, 2014 Aug.
Article
en En
| MEDLINE
| ID: mdl-24934864
ABSTRACT
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Polietilenglicoles
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Asparaginasa
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Proteínas Recombinantes
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Escherichia coli
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Leucemia-Linfoma Linfoblástico de Células Precursoras
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Cancer Chemother Pharmacol
Año:
2014
Tipo del documento:
Article