PMID- 15828851 OWN - NLM STAT- MEDLINE DCOM- 20050803 LR - 20220330 IS - 0312-5963 (Print) IS - 0312-5963 (Linking) VI - 44 IP - 4 DP - 2005 TI - Pharmacokinetic/pharmacodynamic relationships of asparaginase formulations: the past, the present and recommendations for the future. PG - 367-93 AB - 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 0.4-0.7 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 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. FAU - Avramis, Vassilios I AU - Avramis VI AD - Division of Hematology/Oncology, Department of Pediatrics, Keck School of Medicine, University of Southern California, Childrens Hospital Los Angeles, Los Angeles, California, USA. vavramis@chla.usc.edu FAU - Panosyan, Eduard H AU - Panosyan EH LA - eng PT - Historical Article PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review PL - Switzerland TA - Clin Pharmacokinet JT - Clinical pharmacokinetics JID - 7606849 RN - 0 (Antineoplastic Agents) RN - 3WJQ0SDW1A (Polyethylene Glycols) RN - 7D96IR0PPM (pegaspargase) RN - EC 3.5.1.1 (Asparaginase) SB - IM MH - Animals MH - Antineoplastic Agents/history/pharmacokinetics/*pharmacology MH - Asparaginase/administration & dosage/history/pharmacokinetics/*pharmacology MH - Child MH - Clinical Trials as Topic MH - Dickeya chrysanthemi/enzymology MH - Drug Administration Schedule MH - Drug Resistance, Neoplasm MH - Escherichia coli/enzymology MH - History, 20th Century MH - History, 21st Century MH - Humans MH - Polyethylene Glycols/administration & dosage/pharmacology MH - Precursor Cell Lymphoblastic Leukemia-Lymphoma/*drug therapy RF - 88 EDAT- 2005/04/15 09:00 MHDA- 2005/08/04 09:00 CRDT- 2005/04/15 09:00 PHST- 2005/04/15 09:00 [pubmed] PHST- 2005/08/04 09:00 [medline] PHST- 2005/04/15 09:00 [entrez] AID - 4443 [pii] AID - 10.2165/00003088-200544040-00003 [doi] PST - ppublish SO - Clin Pharmacokinet. 2005;44(4):367-93. doi: 10.2165/00003088-200544040-00003.