A Population Model Describing the Activity-time Course of Pegylated Asparaginase in Children
Hempel, Georg; Lanvers-Kaminsky, Claudia; Ahlke, Elvira; Müller, Hans-J.; Würthwein, Gudrun; Boos, Joachim
Institut für Pharmazeutische und Medizinische Chemie, Universitaet Muenster, GermanyPEG-Asparaginase is an important part of many treatment protocols for ALL. In many centres Asparaginase activity is controlled after administration of PEG-asparaginase. However, a predictive pharmacokinetic model necessary for dose adjustment or better decision making when to switch to another preparation is lacking. Therefore, we have analysed 1189 serum activity measurements in 185 children from the ALL-BFM 95 study. Patients received 500, 1000 or 2500 U/m2 PEG-Asp on up to 9 occasions. Serum samples were analysed using a semi-automatic enzymatic assay with a limit of quantification of 2 U/l [C. Lanvers et al. Anal. Biochem. 2002, 309, 117-126]. Data analysis was done using nonlinear mixed effects modelling (NONMEM Vers. V). A Michaelis-Menten model reflected the data sufficiently for one dose alone [H.J. Mueller et al. Cancer Chemother. Pharmacol. 2002, 49, 149-154], but not with all dosing groups analysed together. The best model applicable to all dosing groups was a one-compartmental model with clearance increasing with time according to the formula: Cl = Cli*exp(0.0853*t) with Cli=initial clearance, and t=time. The parameters found were: Volume of distribution (V) 1.05 ± 27.3% l/m2 , Cli 60.3 ± 70.8% ml/(day m2) (mean ± interindividual variability). Interoccasion variability was substantial with 0.223 l/m2 for V and 37.7 ml/(day m2) Cli, respectively. About 30% of the patients show a high clearance probably due to the development of inactivating antibodies. Drug monitoring of serum PEG-Asparaginase activity is required to identify these patients who do not benefit from PEG-Asp therapy. The model should help to reduce the number of required serum samples per patient.