Population Pharmacokinetics to Model the Time-Varying Clearance of the PEGylated Asparaginase Oncaspar® in Children with Acute Lymphoblastic Leukemia
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Background and Objectives
The pharmacokinetics of the polyethylene glycol (PEG)-conjugated asparaginase Oncaspar® are characterized by an increase in elimination over time. The focus of our analysis is the better understanding of this time-dependency.
In paediatric acute lymphoblastic leukemia therapy (AIEOP-BFM ALL 2009), two administrations of Oncaspar® (2500 U/m2 intravenously) in induction phase (14-day interval) and one single administration in reinduction were followed by weekly monitoring of asparaginase activity. Non-linear mixed-effects modeling techniques (NONMEM) were used. Samples indicating immunological inactivation were excluded to describe the pharmacokinetics under standard conditions. Models with time-constant or time-varying clearance (CL) as well as transit compartment models with an increase in CL over a chain of compartments were investigated.
Models with time-constant elimination could not adequately describe 6107 asparaginase activities from 1342 patients. Implementing a time-varying CL improved the fit. Modeling an increase of CL over time after dose (Emax- and Weibull-functions) were superior to models with an increase of CL over time after the first administration. However, a transit compartment model came out to be the best structural model.
The increase in elimination of PEGylated asparaginase appears to be driven by physicochemical processes that are drug-related. The observed hydrolytically in vitro instability of the drug leads to the hypothesis that this increase in CL might be due to an in vivo hydrolysis of the instable ester bond between PEG and the enzyme combined with an increased elimination of the partly de-PEGylated enzyme (Trial registered at www.clinicaltrials.gov, NCT0111744).
KeywordsAcute Lymphoblastic Leukemia Bayesian Information Criterion Asparaginase Objective Function Value Visual Predictive Check
We wish to thank Andrea Rüffer, Petra Schulze Westhof, Sandra Schulz for laboratory assistance and Jana Golitsch for documentation and data management.
Compliance with Ethical Standards
Limited research support (for data collection and safety reporting) for the ALL-BFM study center in Kiel (Germany) has been received from medac GmbH, Sigma-Tau, Baxter and Jazz Pharmaceuticals. The pharmacological laboratory at the department of Paediatric Haematology and Oncology at the University Hospital Münster received limited research support for drug monitoring from medac GmbH, Sigma-Tau and Baxter. No sources of funding were used to assist with the preparation of this manuscript.
Conflicts of interest
J Boos served personally as a consultant and participated in advisory as well as in safety boards for the medac GmbH. He received support for travel from Eusa Pharma, Jazz Pharmaceuticals, Baxalta and Shire. For medac GmbH, Eusa Pharma, Jazz Pharmaceuticals, Baxalta, Shire and Sigma-Tau he held invited lectures. In addition, institutional grants in the context of ASNase drug monitoring from more or less all ASNase providers contributed to the therapeutic drug monitoring program, including the medac GmbH, Eusa Pharma, Jazz Pharmaceuticals, Baxalta, Shire, Sigma-Tau (all representing the varying marketing authorization holders of E. coli ASNase, PEG-ASNase and Erwinase). G. Hempel received research grants from the medac GmbH, the former distributor of PEG-ASNase in Germany, for analyzing the pharmacokinetics of different ASNase formulations. C. Lanvers-Kaminsky received consulting fees from ERYTECH. G. Würthwein, S. Gastine, A. Möricke and M. O. Karlsson have no potential conflicts of interest to declare.
The AIEOP-BFM ALL 2009 trial (EudraCT Number 2007-004270-43) was approved by the competent ethics committees of the national coordinating centers. This trial was registered at www.clinicaltrials.gov with the identifier NCT01117441. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from the parents or guardians of each patient included in the study.
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