Population Pharmacokinetics to Model the Time-Varying Clearance of the PEGylated Asparaginase Oncaspar® in Children with Acute Lymphoblastic Leukemia

Würthwein G, Lanvers-Kaminsky C, Hempel G, Gastine S, Möricke A, Schrappe M, Karlsson M, Boos J

Abstract

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. Methods: 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. Results: 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. Conclusion: 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).