Pharmacokinetic/Pharmacodynamic Relationships of Asparaginase Formulations

Abstract

The discovery of the tumour-inhibitory properties of asparaginase began 50 years ago with the observation that guinea-pig serum-treated lymphoma-bearing mice underwent rapid and often complete regression. Soon afterwards, the asparaginase of bacterial origin was isolated. The asparaginases of bacterial origin induce anti-asparaginase neutralising antibodies in a large proportion of patients (44-60%), thus negating the specific enzymatic activity and resulting in failure of the target amino acid deamination in serum. There is immunological cross-reaction between the antibodies against various formulations of native Escherichia coli-asparaginase and polyethylene glycol (PEG)-asparaginases, but not to Erwinia asparaginase, as suggested by laboratory preclinical findings. This evidence was strongly inferred from the interim analyses in the Children's Cancer Group (CCG)-1961 study. Thus, anti-E. coli or PEG-asparaginase antibodies seropositive patients may benefit from the Erwinia asparaginase. The inter-relationships between asparaginase activity, asparagine (ASN) and glutamine deamination remain largely unexplored in patients. Studies have shown that ASN depletion is insufficient to induce apoptosis in T lymphoblasts in vitro and that the inhibitory concentration of CEM T-cell line is correlated with the asparaginase concentration responsible for 50% glutamine deamination. The optimal catalysis of ASN and glutamine deamination in serum by asparaginase induces apoptosis of leukaemic lymphoblasts. The percentage of ASN and glutamine deamination was predicted by asparaginase activity. Asparaginase activity of 0.1 IU/mL provided insufficient depletion of both amino acids in high-risk acute lymphoblastic leukaemia (ALL) patients. With increasing glutamine deamination, mean asparaginase activities and percentages of post-treatment samples with effective ASN depletion (<3 micromol/L) increase. Both glutamine and ASN deamination are predicted by asparaginase activity. Further population analyses resulted in identification of sigmoid relationships between asparaginase levels and post-treatment glutamine and ASN deamination.Furthermore, pharmacodynamic analyses strongly suggested that >/=90% deamination of glutamine must occur before optimal ASN deamination takes place, due to the de novo ASN biosynthesis by the liver. These pharmacodynamic results from the best-fit population pharmacokinetic/pharmacodynamic model obtained from nonlinear mixed effects model pharmacodynamic analyses for standard-risk ALL patients are similar. These analyses produced the following results: (i) asparaginase activity </=0.4 IU/mL provided insufficient deamination of ASN, whereas >0.4-0.7 IU/mL was required for optimal (90%) ASN and glutamine deamination; and (ii) deamination of glutamine is dependent on asparaginase activity and it correlates with enhanced serum ASN deamination. Thus, glutamine deamination enhances asparaginase efficacy in ALL patients. Deamination of ASN >/=90% of control or ASN concentration <3 micromol/L may be associated with...

Identification and Structural Analysis of an l-Asparaginase Enzyme from Guinea Pig with Putative Tumor Cell Killing Properties

“…A reduced but still present immune intolerance remains because of the foreign origin of these drugs. Furthermore, the enzyme can still be cleared from the blood and an immune reaction elicited because of antibody formation against PEG (11)(12)(13). This suggests that a more human-like enzyme, which would be less immunogenic, could be a superior replacement (14 -16).…”

Purification and Biochemical Characterization of Native and Pegylated Form of L-Asparaginase from &lt;i&gt;Aspergillus terreus&lt;/i&gt; and Evaluation of Its Antiproliferative Activity

“…The molecular weight found here for the enzyme was 136 kDa, similar value has been described to E. coli L-asparaginase, 134 kDa. However, the Km value of native L-asparaginase was found to be 2.42 mM, while that from E. coli is 0.0125 mM [15]. It shows that the L-asparaginase from A. terreus has less affinity for asparagine than Lasparaginase from E. coli but the L-asparaginase from A. terreus was capable to inhibit the prolifiration of leukemia cells.…”

Comparative Characterization of L-Asparaginase Extracted From Plant and Microbial Sources

“…Hence, the cancer cells die as a result of asparagine starvation 3,4 . It is available under brand names such as Elspar, Oncaspar, Erwinaze, Leunase, Medac, Crasnitin, Paronal, Kidrolase, Acrylaway, PreventASe, Cristanaspase and PEG-asparaginase 5,6 . It is a tetrameric protein produced and used by the organisms for the storage and transport of the nitrogen which is then utilized for the protein synthesis 7 .…”