PEGylated Asparaginase in Children with Acute Lymphoblastic Leukemia Treated within the AIEOP-BFM ALL 2009 Trial: Population Pharmacokinetics and Drug Exposure

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

PEGylated Asparaginase in Children with Acute Lymphoblastic Leukemia Treated within the AIEOP-BFM ALL 2009 Trial: Population Pharmacokinetics and Drug Exposure

Popis výsledku v původním jazyce

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: &lt;= 600/&gt; 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.

Název v anglickém jazyce

PEGylated Asparaginase in Children with Acute Lymphoblastic Leukemia Treated within the AIEOP-BFM ALL 2009 Trial: Population Pharmacokinetics and Drug Exposure

Popis výsledku anglicky

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: &lt;= 600/&gt; 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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30205 - Hematology

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

European Journal of Drug Metabolism and Pharmacokinetics

ISSN

0378-7966

e-ISSN

2107-0180

Svazek periodika

50

Číslo periodika v rámci svazku

6

Stát vydavatele periodika

FR - Francouzská republika

Počet stran výsledku

14

Strana od-do

501-514

Kód UT WoS článku

001553626400001

EID výsledku v databázi Scopus

2-s2.0-105013586006