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Published on: September 18, 2013
PEGylated Asparaginase in Children with Acute Lymphoblastic Leukemia Treated within the AIEOP-BFM ALL 2009 Trial:
Gudrun Würthwein1, Christian Siebel2, Claudia Lanvers-Kaminsky2
1Department of Paediatric Haematology and Oncology, University Children's Hospital Muenster, Muenster, Germany. wurthwg@uni-muenster.de.
Insights
This study models polyethylene glycol-conjugated asparaginase pharmacokinetics in children with acute lymphoblastic leukemia, revealing treatment phase impacts on drug levels and accumulation. The developed model aids in optimizing dosing schedules and calculating individual dose-intensity parameters (DIPs).
Area of Science:
- Pharmacokinetics and Pharmacodynamics
- Pediatric Oncology
- Drug Metabolism and Disposition
Background:
- The AIEOP-BFM ALL 2009 trial investigated polyethylene glycol-conjugated asparaginase (PEG-ASNase) in pediatric acute lymphoblastic leukemia.
- Understanding PEG-ASNase pharmacokinetics is crucial for optimizing treatment efficacy and minimizing toxicity.
- Previous models may not fully capture pharmacokinetic variability across different treatment phases and patient groups.
Purpose of the Study:
- To develop a population pharmacokinetic (popPK) model for PEG-ASNase in pediatric ALL patients across all treatment phases.
- To characterize the impact of anti-PEG and anti-asparaginase antibodies on PEG-ASNase pharmacokinetics.
- To derive individual dose-intensity parameters (DIPs) and assess their relationship with clinical outcomes.
Main Methods:
- A popPK model was extended to analyze PEG-ASNase data from 2535 German/Czech patients and validated in 1603 Italian patients.
- The model incorporated data from 279 Australian patients for DIP derivation.
- Assays included the aspartic acid β-hydroxamate (AHA) assay and medac asparaginase activity test (MAAT); allergic reactions and silent inactivation were exclusion criteria.
Main Results:
- Pharmacokinetics varied significantly by treatment phase, with up to 60% lower clearance and 30% lower volume of distribution compared to initial doses.
- Drug accumulation was observed after repetitive doses, exceeding linear extrapolation predictions.
- High pre-existing anti-PEG-antibody levels impacted induction phase clearance; other antibody effects were not significant unless leading to inactivation or allergy.
Conclusions:
- The developed popPK model accurately describes PEG-ASNase pharmacokinetics across all treatment phases and patient groups, integrating antibody impacts.
- The model enables strategic optimization of clinical trial schedules and precise calculation of individual dose-intensity parameters (DIPs).
- This approach supports personalized dosing strategies for PEG-ASNase in pediatric ALL treatment.
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:
Children with acute lymphoblastic leukemia received 1-10 weekly or biweekly repetitive doses (2500 U/m2/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.
