Comparative pharmacokinetic/pharmacodynamic characterisation of a new pegylated recombinant E. coli l-asparaginase preparation (MC0609) in Beagle dog

Borghorst, Stephan; Hempel, Georg; Poppenborg, Sabine; Franke, D.; König, Thorsten; Baumgart, Joachim

doi:10.1007/s00280-014-2506-9

Cited by 8 publications

(9 citation statements)

References 19 publications

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“…The well-known PK profile (increased elimination with time) of pegaspargase was confirmed in this study (Panetta et al, 2009;Hempel et al, 2010;Borghorst et al, 2014) (Fig. 4).…”

Section: Discussionsupporting

confidence: 81%

“…4). In contrast, constant (linear) elimination of PEG-rASNase MC0609 activity resulted in a prolonged enzymatic activity in serum of mice and in a significantly longer depletion of L-asparagine in peripheral blood of dogs compared to pegaspargase (Borghorst et al, 2014).…”

Section: Discussionmentioning

confidence: 72%

“…4B and D) which was formerly observed in the Beagle dog after single dose i.v. administration (Borghorst et al, 2014). An early, accelerated decrease in ASNase activity was observed in 1/8 pegaspargase treated animals (not PEG-Diol pre-sensitised), demonstrating no measurable serum ASNase activity from day +17 on (Fig.…”

Section: Pk-study: Pharmacokinetics Of Peg-rasnase and Pegaspargasementioning

confidence: 97%

“…Serum ASNase levels were determined by hydrolysis of aspartic acid-β-hydroxamate and detection of the hydroxylamine after derivatisation with 8-hydroxychinoline and oxidation to indoxine by ultraviolet light (AHA assay) (Lanvers et al, 2002;Borghorst et al, 2014).…”

Section: Determination Of Asparaginase Activitymentioning

confidence: 99%

“…Preclinical studies showed striking differences in the pharmakocinetics (PK) and pharmacodynamics (PD) properties of PEG-rASNase MC0609 compared to Oncaspar ® in the Beagle dog. The PK of PEG-rASNase MC0609 is characterized by a prolonged and dose-dependent exposition of enzymatic activity and a significantly longer depletion of L-asparagine in peripheral blood (Borghorst et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Impact of anti-PEG IgM antibodies on the pharmacokinetics of pegylated asparaginase preparations in mice

Poppenborg

Wittmann²,

Walther

et al. 2016

European Journal of Pharmaceutical Sciences

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“…The well-known PK profile (increased elimination with time) of pegaspargase was confirmed in this study (Panetta et al, 2009;Hempel et al, 2010;Borghorst et al, 2014) (Fig. 4).…”

Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 72%

Section: Pk-study: Pharmacokinetics Of Peg-rasnase and Pegaspargasementioning

confidence: 97%

Section: Determination Of Asparaginase Activitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Impact of anti-PEG IgM antibodies on the pharmacokinetics of pegylated asparaginase preparations in mice

Poppenborg

Wittmann²,

Walther

et al. 2016

European Journal of Pharmaceutical Sciences

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Improved pharmacokinetic and pharmacodynamic profile of a novel PEGylated native Erwinia chrysanthemi L-Asparaginase

Modi¹,

Gervais²

2021

Invest New Drugs

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SummaryIntroduction. Erwinase® (native Erwinia chrysanthemi L-Asparaginase (nErA)) is an approved second-line treatment for acute lymphoblastic leukaemia (ALL) in children and adolescents, who develop hypersensitivity or neutralising antibodies to E.coli derived L-Asparaginases (ASNases). However, nErA has a short in vivo half-life requiring frequent dosing schedules in patients. In this study, nErA was covalently conjugated to PEG molecules with the aim of extending its half-life in vivo. Methods. Firstly, efficacy of this novel product PEG-nErA was investigated on human ALL cell lines (Jurkat, CCRF-CEM and CCRF-HSB2), in vitro. Secondly, its pharmacokinetic (PK) and pharmacodynamic (PD) characteristics were determined, in vivo (12 rats in each group). Results. It was found that the specific activity (U/mg of enzyme) and the kinetic constant (KM) of nErA remained unaltered post PEGylation. PEG-nErA was shown to have similar cytotoxicity to nErA (IC50: 0.06–0.17 U/mL) on human ALL cell lines, in vitro. Further, when compared to nErA, PEG-nErA showed a significantly improved half-life in vivo, which meant that L-Asparagine (Asn) levels in plasma remained depleted for up to 25 days with a four-fold lower dose (100 U/kg) compared with 72 h for nErA at 400 U/kg dose. Conclusion. Overall, this next generation product PEG-nErA (with improved PK and PD characteristics compared to nErA) would bring a significant advantage to the therapeutic needs of ALL patients and should be further explored in clinical trials.

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Development of a Lyophilized Formulation of Pegaspargase and Comparability Versus Liquid Pegaspargase

Faschinger¹,

Sessler²

2019

Adv Ther

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IntroductionPegaspargase, a pegylated asparaginase, is a core component in the treatment of acute lymphoblastic leukemia. Pegaspargase in liquid form has a limited shelf life of 8 months due to depegylation, leading to changes in purity and potency over time. Lyophilization is an approach that can improve the stability of biological drug conjugates.MethodsHere we describe the development of a lyophilized formulation of pegaspargase and present results of a series of tests demonstrating that the lyophilized form has comparable physicochemical properties to the liquid form.ResultsStability tests of critical quality attributes, including purity, potency, aggregates and total free polyethylene glycol, demonstrate that lyophilized pegaspargase remains stable for at least 3 years, with optimum stability achieved with storage under refrigerated conditions (2–8 °C).ConclusionsLyophilization improved the stability of pegaspargase without altering other physicochemical properties, permitting a prolonged shelf life of at least 2 years when stored at 2–8 °C. This may enable greater storage flexibility and allow for better management of pegaspargase.FundingStudy Sponsor: Baxalta (now part of Takeda). Publication Sponsor: Servier Affaires Médicales.Electronic supplementary materialThe online version of this article (10.1007/s12325-019-00988-5) contains supplementary material, which is available to authorized users.

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Comparative pharmacokinetic/pharmacodynamic characterisation of a new pegylated recombinant E. coli l-asparaginase preparation (MC0609) in Beagle dog

Abstract: The new pegylated recombinant L-asparaginase preparation MC0609 revealed striking differences in PK/PD properties compared with Oncaspar(®) in rat and dog.

Cited by 8 publications

References 19 publications

Impact of anti-PEG IgM antibodies on the pharmacokinetics of pegylated asparaginase preparations in mice

Impact of anti-PEG IgM antibodies on the pharmacokinetics of pegylated asparaginase preparations in mice

Improved pharmacokinetic and pharmacodynamic profile of a novel PEGylated native Erwinia chrysanthemi L-Asparaginase

Development of a Lyophilized Formulation of Pegaspargase and Comparability Versus Liquid Pegaspargase

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