Comparison of intramuscular therapy with Erwinia asparaginase and asparaginase Medac: pharmacokinetics, pharmacodynamics, formation of antibodies and influence on the coagulation system.
Asparaginase comes from different biological sources and the various preparations have different pharmacokinetic properties, and their tendency to induce side-effects is different. Erwinia asparaginase (ASNase) has a shorter half-life than the Escherichia coli preparations, and it has been reported to be less immunogenic than the E. coli preparations and to induce fewer coagulation disorders. Children with newly diagnosed acute lymphoblastic leukaemia (ALL) were included in this study. Twenty-seven patients were treated with Erwinia ASNase (induction therapy 30.000 IU/m2/d i.m. for 10 d, and re-induction therapy 30.000 IU/m2 twice a week for 2 weeks) and 15 were treated with ASNase Medac (induction therapy 1.000 IU/m2/d i.m. for 10 d, and re-induction therapy 5.000 IU/m2 i.m. twice a week for 2 weeks). Blood samples were drawn to determine enzyme activity, l-asparagine, anti-asparaginase antibodies, and coagulation parameters. After i.m. administration, Erwinia ASNase displayed a protracted absorption phase compared to ASNase Medac. The mean bioavailability after i.m. administration was 27% for Erwinia ASNase and 45% for ASNase Medac respectively. Mean trough enzyme activities during induction therapy were Erwinia ASNase 1748 IU/l and ASNase Medac 272 IU/l, and during re-induction therapy Erwinia ASNase 83 IU/l and ASNase Medac 147 IU/l. We conclude that in this setting, therapy with ASNase Medac resulted in sufficient treatment during both phases of therapy, whereas treatment with Erwinia ASNase resulted in unnecessarily intense therapy during the induction phase and insufficient treatment during the re-induction phase. There was no significant difference in the incidence of antibody formation, and therapy with Erwinia ASNase resulted in a more pronounced influence on the coagulation parameters than therapy with ASNase Medac.
Albertsen
B K
BK
Centre for Clinical Pharmacology, Department of Pharmacology, The Bartholin Building, University of Aarhus, 8000 Aarhus C, Denmark. bka@farm.au.dk
Schrøder
H
H
Ingerslev
J
J
Jakobsen
P
P
Avramis
V I
VI
Müller
H J
HJ
Carlsen
N T
NT
Schmiegelow
K
K
D000042:Absorption; D000906:Antibodies / Q000097:blood; D001215:Asparaginase / Q000097:blood / Q000276:immunology / Q000627:therapeutic use*; D001216:Asparagine / Q000097:blood; D001426:Bacterial Proteins / Q000097:blood / Q000276:immunology / Q000627:therapeutic use*; D001682:Biological Availability; D001777:Blood Coagulation; D002648:Child; D004305:Dose-Response Relationship, Drug; D004885:Erwinia / Q000201:enzymology*; D004926:Escherichia coli / Q000201:enzymology*; D006801:Humans; D007273:Injections, Intramuscular; D008099:Liver / Q000503:physiopathology; D008111:Liver Function Tests; D010865:Pilot Projects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D012044:Regression Analysis; D012074:Remission Induction
D000906:Antibodies; D001426:Bacterial Proteins; D001216:Asparagine; D001215:Asparaginase