Comparison of Native E. coli and PEG Asparaginase Pharmacokinetics and Pharmacodynamics in Pediatric Acute Lymphoblastic Leukemia

Abstract

Asparaginase is used routinely in frontline clinical trials for the treatment of childhood acute lymphoblastic leukemia (ALL). The goals of this study were to assess the pharmacokinetics and pharmacodynamics of asparaginase and to mathematically model the dynamics between asparaginase and asparagine in relapsed ALL. Forty children were randomized to receive either native or PEGylated (PEG) Escherichia coli asparaginase during reinduction therapy. Serial plasma asparaginase and asparagine, cerebrospinal fluid (CSF) asparagine, and serum anti-asparaginase antibody samples were collected. The asparaginase clearance was higher (P=.001) for native vs. PEG asparaginase. Patients with antibodies to PEG asparaginase had faster PEG clearance (P=.004) than antibody-negative patients. Patients who were positive for antibodies had higher CSF asparagine than those who were negative (P=.04). The modeling suggests that by modifying dosages, comparable asparagine depletion should be achievable with both preparations. At relapse, there were significant pharmacokinetic and pharmacodynamic differences due to asparaginase preparation and antibody status.

Effect of Premedications in a Murine Model of Asparaginase Hypersensitivity

“…5B) compared with other pretreatment groups. This is similar to the accelerated asparaginase clearance seen in pediatric patients with relapsed ALL receiving E. coli asparaginase and negative for anti-asparaginase IgG antibodies (Panetta et al, 2009).…”

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

“…In addition, immunologic responses to all asparaginase preparations are associated with formation of neutralizing antibodies against the enzyme that may or may not be associated with a symptomatic allergy. 19,21,22,42,43 The primary role of Erwinia asparaginase in the treatment of ALL has been to replace native E coli asparaginase or pegaspargase after patients exhibit allergic reactions to either or both preparations. 25,44,45 In large randomized clinical trials, administration of Erwinia asparaginase once or twice a week was associated with inferior outcomes as compared with E coli asparaginase 40,46 when administered on identical dosing schedules.…”

“…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.…”

Purification and Biochemical Characterization of Native and Pegylated Form of L-Asparaginase from <i>Aspergillus terreus</i> and Evaluation of Its Antiproliferative Activity

“…It is important to know that the half-lives of E. coli asparaginase linked to PEG are longer than the native enzyme [3,17]. Herein the pegylated-L-asparaginase was resistant to trypsin, a cysteine protease, and was more thermostable than the native enzyme, as well maintained 93% of the original activity.…”

“…Current studies of L-asparaginase therapy have also started in adults [2]. The effect and half-life of L-asparaginase depends on some factors such as antibody formation, plasmatic proteases, formation of asparagine via asparagine synthetase and microbial source [3]. Over the years, several bacterial L-asparaginases have been reported and only a few reports about L-asparaginase produced by filamentous fungi have been made.…”