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.

Biochemistry Department and Cancer Centre for Children The Children's Hospital at Westmead Sydney NSW Australia

Department of Paediatric Haematology and Oncology Charles University and University Hospital Motol Prague Czech Republic

Department of Paediatric Haematology and Oncology University Children's Hospital Muenster Muenster Germany

Department of Paediatrics Christian Albrechts University Kiel and University Medical Centre Schleswig Holstein Kiel Germany

Laboratory of Cancer Pharmacology Department of Oncology Istituto di Ricerche Farmacologiche Mario Negri IRCCS Milan Italy

Pediatric Hematology Oncology Unit IRCCS San Gerardo University of Milano Bicocca Monza Italy

Sydney Pharmacy School Faculty of Health and Medicine University of Sydney Sydney NSW Australia

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