Background and Objectives: Besides allergic reactions, antibodies against polyethylene glycol (PEG) have been associated with reduced PEG-asparaginase (PEG-ASNase) activity. Population pharmacokinetics (popPK) allow for an in-depth investigation of the influence of anti-PEG antibodies on PEG-ASNase pharmacokinetics. Methods: PEG-ASNase activity (6261 samples) and anti-PEG antibodies (2082/6412 samples prior to/post administration) in 1444 children with acute lymphoblastic leukaemia treated in the AIEOP-BFM ALL 2009 trial were evaluated. Patients received two doses of PEG-ASNase during induction (2500 U/m2, intravenous, biweekly) and a third dose during reinduction treatment. Anti-PEG IgG and IgM measured prior to and post administration were explored for their influence on the initial clearance of PEG-ASNase using a previously established popPK model. Categorical and continuous antibody data, including each isotype individually as well as in combination, were assessed. Results: High pre-existing levels of anti-PEG antibodies increase the initial drug clearance. Analysed separately, both anti-PEG IgGprior and IgMprior were significant covariates; the stronger effect was observed for anti-PEG IgMprior. Hockey stick models best described the data. For anti-PEG IgMprior, each additional log unit above the estimated cut point was related to a 41.4% increase in initial clearance after the first dose in induction. Antibody levels below the cut point were not associated with an effect on clearance. The combination of both isotypes did not provide additional information compared to anti-PEG IgMprior alone. Antibody levels post administration were not associated with an effect on clearance. Conclusion: Pre-existing antibodies against PEG-ASNase significantly increased the initial clearance in a subgroup of patients showing high antibody levels. (Trial registration: EU clinical trials register; EudraCT No: 2007-004270-43; first registered 23 October 2009.)
Siebel, C., Lanvers-Kaminsky, C., Alten, J., Smisek, P., Nath, C., Rizzari, C., et al. (2022). Impact of Antibodies Against Polyethylene Glycol on the Pharmacokinetics of PEGylated Asparaginase in Children with Acute Lymphoblastic Leukaemia: A Population Pharmacokinetic Approach. EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS, 47(2), 187-198 [10.1007/s13318-021-00741-w].
Impact of Antibodies Against Polyethylene Glycol on the Pharmacokinetics of PEGylated Asparaginase in Children with Acute Lymphoblastic Leukaemia: A Population Pharmacokinetic Approach
Rizzari C.;
2022
Abstract
Background and Objectives: Besides allergic reactions, antibodies against polyethylene glycol (PEG) have been associated with reduced PEG-asparaginase (PEG-ASNase) activity. Population pharmacokinetics (popPK) allow for an in-depth investigation of the influence of anti-PEG antibodies on PEG-ASNase pharmacokinetics. Methods: PEG-ASNase activity (6261 samples) and anti-PEG antibodies (2082/6412 samples prior to/post administration) in 1444 children with acute lymphoblastic leukaemia treated in the AIEOP-BFM ALL 2009 trial were evaluated. Patients received two doses of PEG-ASNase during induction (2500 U/m2, intravenous, biweekly) and a third dose during reinduction treatment. Anti-PEG IgG and IgM measured prior to and post administration were explored for their influence on the initial clearance of PEG-ASNase using a previously established popPK model. Categorical and continuous antibody data, including each isotype individually as well as in combination, were assessed. Results: High pre-existing levels of anti-PEG antibodies increase the initial drug clearance. Analysed separately, both anti-PEG IgGprior and IgMprior were significant covariates; the stronger effect was observed for anti-PEG IgMprior. Hockey stick models best described the data. For anti-PEG IgMprior, each additional log unit above the estimated cut point was related to a 41.4% increase in initial clearance after the first dose in induction. Antibody levels below the cut point were not associated with an effect on clearance. The combination of both isotypes did not provide additional information compared to anti-PEG IgMprior alone. Antibody levels post administration were not associated with an effect on clearance. Conclusion: Pre-existing antibodies against PEG-ASNase significantly increased the initial clearance in a subgroup of patients showing high antibody levels. (Trial registration: EU clinical trials register; EudraCT No: 2007-004270-43; first registered 23 October 2009.)
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