Comparison of intramuscular therapy with Erwinia asparaginase and asparaginase Medac: pharmacokinetics, pharmacodynamics, formation of antibodies and influence on the coagulation system

Abstract

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.

Erwinia asparaginase achieves therapeutic activity after pegaspargase allergy: a report from the Children’s Oncology Group

“…Although Erwinia asparaginase was first introduced into clinical trials in the early 1970s, 49 prior clinical pharmacokinetic studies of this preparation of the enzyme are limited to only two investigations involving relatively small patient numbers. 17,18 The time course of serum asparaginase activity resulting from intramuscular injection of a single 25 000-IU/m 2 dose of Erwinia asparaginase to pediatric ALL patients was first reported by Asselin et al 17 They found that the mean terminal phase half-life of asparaginase activity was 15.6 6 3.1 hours for intramuscular Erwinia asparaginase in 10 patients. In our study, the overall mean apparent biological half-life of asparaginase activity for the entire group of 54 patients with evaluable course 1 pharmacokinetic data was 16.5 6 6.4 hours, in excellent agreement with this value.…”

“…18 Asparaginase activity decayed with a mean half-life of 6.4 6 1.9 hours when the enzyme was given by the intravenous route. The mean total body clearance of Erwinia asparaginase was 0.…”

“…Pegaspargase has been the more commonly used product because it requires less frequent administration than E coli asparaginase as a consequence of its longer biological half-life and because of its lower immunogenicity. [17][18][19][20][21] A third preparation, Erwinia asparaginase, derived from the bacterium Erwinia chrysanthemi, was not commercially available in the United States during the conduct of this study but was available on a compassionate use basis.…”

Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation

“…18 This cut-off of ≥ 0.1 IU/mL has been confirmed and used in many clinical trials. 9,19,[22][23][24] The question arises whether a lower threshold, for example of 0.05 IU/mL, also leads to complete asparagine depletion. Rizzari and colleagues showed that trough asparaginase activity levels of < 0.05 IU/mL, obtained either with native E. Coli or Erwinia asparaginase, resulted in serum and CSF asparagine depletion in children with ALL.…”

Mutations in Subunit Interface and B-cell Epitopes Improve Antileukemic Activities of Escherichia coli Asparaginase-II

“…This leads to inadequate plasma levels of the EcA, which limit its efficacy. However, it was reported that not all patients with hypersensitivity develop ADAs, and not all patients who develop ADAs exhibit hypersensitivity (16,17). Another serious drawback of the anti-leukemic drugs is their generalized cytotoxic effects on healthy cells along with leukemic cells.…”