Gudrun Würthwein, Christian Siebel, Claudia Lanvers-Kaminsky, Petr Smisek, Christa E Nath, Cristina Matteo, Carmelo Rizzari, Martin Schrappe, Joachim Boos
{"title":"在aiop - bfm ALL 2009试验中治疗急性淋巴细胞白血病儿童的聚乙二醇化天冬酰胺酶：人群药代动力学和药物暴露。","authors":"Gudrun Würthwein, Christian Siebel, Claudia Lanvers-Kaminsky, Petr Smisek, Christa E Nath, Cristina Matteo, Carmelo Rizzari, Martin Schrappe, Joachim Boos","doi":"10.1007/s13318-025-00962-3","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and objectives: </strong>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.</p><p><strong>Methods: </strong>Children with acute lymphoblastic leukemia received 1-10 weekly or biweekly repetitive doses (2500 U/m<sup>2</sup>/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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p><p><strong>Trial registration: </strong>EU clinical trails register; European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) Number 2007-004270-43.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":2.4000,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"PEGylated Asparaginase in Children with Acute Lymphoblastic Leukemia Treated within the AIEOP-BFM ALL 2009 Trial: Population Pharmacokinetics and Drug Exposure.\",\"authors\":\"Gudrun Würthwein, Christian Siebel, Claudia Lanvers-Kaminsky, Petr Smisek, Christa E Nath, Cristina Matteo, Carmelo Rizzari, Martin Schrappe, Joachim Boos\",\"doi\":\"10.1007/s13318-025-00962-3\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and objectives: </strong>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.</p><p><strong>Methods: </strong>Children with acute lymphoblastic leukemia received 1-10 weekly or biweekly repetitive doses (2500 U/m<sup>2</sup>/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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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. 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PEGylated Asparaginase in Children with Acute Lymphoblastic Leukemia Treated within the AIEOP-BFM ALL 2009 Trial: Population Pharmacokinetics and Drug Exposure.
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.
期刊介绍：
Hepatology International is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal focuses mainly on new and emerging diagnostic and treatment options, protocols and molecular and cellular basis of disease pathogenesis, new technologies, in liver and biliary sciences.
Hepatology International publishes original research articles related to clinical care and basic research; review articles; consensus guidelines for diagnosis and treatment; invited editorials, and controversies in contemporary issues. The journal does not publish case reports.
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