PEGylated Asparaginase in Children with Acute Lymphoblastic Leukemia Treated within the AIEOP-BFM ALL 2009 Trial: Population Pharmacokinetics and Drug Exposure
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064203%3A_____%2F25%3A10500739" target="_blank" >RIV/00064203:_____/25:10500739 - isvavai.cz</a>
Result on the web
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=oI7IIc0vjv" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=oI7IIc0vjv</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1007/s13318-025-00962-3" target="_blank" >10.1007/s13318-025-00962-3</a>
Alternative languages
Result language
angličtina
Original language name
PEGylated Asparaginase in Children with Acute Lymphoblastic Leukemia Treated within the AIEOP-BFM ALL 2009 Trial: Population Pharmacokinetics and Drug Exposure
Original language description
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/m(2)/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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30205 - Hematology
Result continuities
Project
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Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
European Journal of Drug Metabolism and Pharmacokinetics
ISSN
0378-7966
e-ISSN
2107-0180
Volume of the periodical
50
Issue of the periodical within the volume
6
Country of publishing house
FR - FRANCE
Number of pages
14
Pages from-to
501-514
UT code for WoS article
001553626400001
EID of the result in the Scopus database
2-s2.0-105013586006