Significant Differences in the Pharmacokinetics of two l-Asparaginase Preparations from Escherichia coli

Abstract

Asparaginase (ASE) preparations from two biological sources (Escherichia coli and Erwinia caratovora) and companies are in clinical use. Current treatment protocols prescribe the dose and schedule but not the preparation to be used. As a rule, E.coli preparations are given (Asparaginase medac, Medac-GmbH, Germany; or Crasnitin, Bayer AG, Germany) unless allergic reactions occur. We initiated a drug-monitoring project to measure asparaginase activity as well as serum amino acid levels in children on the acute lymphoblastic leukemia/non-Hodgkin lymphoma Berlin-Frankfurt-Munster study group 90 (ALL/ NHL-BFM 90) treatment protocols. Samples were taken immediately prior to the application and additionally on the occasion of routine diagnostic punctures. In protocol 1, the dose administered was 10 000U/m2 every 3 days (days 12-33). Asparaginase activity was significantly higher in children treated with Asparaginase medac (162 samples/38 patients: median 441 U/l) than in children on Crasnitin (49 samples/10 patients: median 79 U/l). The serum asparagine levels ranged around the detection limit (0.1 µM) in both groups. While glutamine was similar (365/368 pM), glutamic acid was elevated in the Asparaginase medac group (77 vs, 146 µM median). The pharmacokinetic calculation of pooled data resulted in a T 1/2 of about 24 h for Asparaginase medac and about 15 h for Crasnitin. There are significant differences between asparaginase preparations even when obtained from E coli. The relatively high activity observed with Asparaginase medac is not necessary to reach complete asparagine depletion. In the discussion about side effects of asparaginase, the preparation should, therefore, be specified in every study and the dosages should be defined taking pharmacokinetic differences into account.