PEGylated Asparaginase in Children with Acute Lymphoblastic Leukemia Treated within the AIEOP-BFM ALL 2009 Trial: Population Pharmacokinetics and Drug Exposure
Year: 2025
Type: article
Abstract: BACKGROUND AND OBJECTIVES: Focusing on pharmacokinetic-derived individual dose-intensity parameter values (DIPs), we modeled the pharmacokinetics of polyethylene glycol-conjugated asparaginase (PEG-ASNase) in all treatment phases and different trial groups of AIEOP-BFM ALL 2009. METHODS: /dose intravenously). A population pharmacokinetic (popPK) model was extended to all phases to describe the pharmacokinetics and the impact of anti-PEG- and anti-asparaginase-antibodies in the German/Czech group (2535 patients, aspartic acid β-hydroxamate (AHA) assay) and validated the model in the Italian group (1603 patients, medac asparaginase activity test (MAAT) assay). DIPs, also for 279 Australian patients, were derived. Allergic reactions and silent inactivation were exclusion criteria. RESULTS: Treatment phase dependency and drug accumulation were modeled by up to -60% lower clearance and -30% lower volume of distribution compared with the first administration in induction. Apart from the impact of high preexisting anti-PEG-antibody levels on clearance in induction, no further impact of antibodies was identified. Independent modelling of the Italian data (conversion factor 1.23/1.42: ≤ 600/> 600 U/L) confirmed the model. Time above 100 U/L correlated to the time-interval between the first and last dose within a phase, whereas the area under the concentration-time curve (AUC) was linked to the cumulative dose showing higher drug accumulation after repetitive doses than expected by linear extrapolation. CONCLUSION: A popPK model was adapted to all phases and different trial groups integrating asparaginase antibodies as long as they did not lead to silent inactivation or allergic reaction. The model allows strategic development of trial schedules and the calculation of intended or realized individual DIPs. TRIAL REGISTRATION: EU clinical trails register; European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) Number 2007-004270-43.
Authors: Gudrun Würthwein, Christian Siebel, Claudia Lanvers-Kaminsky, Petr Smisek, Christa E. Nath, Cristina Matteo, Carmelo Rizzari, Martin Schrappe, Joachim Boos, The AIEOP-BFM ALL 2009 Asparaginase Working Party
Institutions: University of Münster, University Hospital Münster, Charles University, University Hospital in Motol, The University of Sydney, Children's Hospital at Westmead, Westmead Hospital, Mario Negri Institute for Pharmacological Research, University of Milano-Bicocca, Christian-Albrechts-Universität zu Kiel, University Hospital Schleswig-Holstein
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $2,690
Award: G1834467801
OpenAlex ID: W4413310819