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Clinical Pharmacokinetics

, Volume 44, Issue 4, pp 367–393 | Cite as

Pharmacokinetic/Pharmacodynamic Relationships of Asparaginase Formulations

The Past, the Present and Recommendations for the Future
  • Vassilios I. Avramis
  • Eduard H. Panosyan
Review Article

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 (s<3 µmol/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 µmol/L may be associated with improved survival in this subset of patients. Our findings support the pharmacodynamic mechanism of PEG-asparaginase for disease control in ALL patients. These results taken together strongly support new experimental approaches for application of population pharmacokinetic/pharmacodynamic analyses to further enhance survival of leukaemia patients.

Keywords

Acute Lymphoblastic Leukaemia Asparaginase Asparaginase Activity Oncaspar Erwinia Asparaginase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

We would like to thank all the paediatric oncologists involved for their contribution and especially Dr Hans-Joachim Müller for his support and help in the preparation of this manuscript.

These studies have been funded in part by CCG, by the TJ Martell Foundation for Leukemia, Cancer, and AIDS Research, (New York, NY, USA), and by a Grant In Aid from Rhone-Poulenc Rorer (RPR). The authors have no conflicts of interest directly relevant to the content of this review. These studies were undertaken for the betterment of our understanding for the optimal use of asparaginase against ALL patients.

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© Adis Data Information BV 2005

Authors and Affiliations

  1. 1.Division of Hematology/Oncology, Department of Pediatrics, Keck School of MedicineUniversity of Southern California, Childrens Hospital Los AngelesLos AngelesUSA

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