A population pharmacokinetic model for pegylated-asparaginase in children

We analysed 1221 serum activity measurements in 168 children from the Berlin-Frankfürt-Münster acute lymphoblastic leukaemia studies, ALL-BFM (Berlin-Frankfürt-Münster) 95 and ALL-BFM REZ, in order to develop a pharmacokinetic model describing the activity-time course of pegylated (PEG)-asparaginase for all dose levels. Patients received 500, 750, 1000 or 2500 U/m² PEG-asparaginase on up to nine occasions. Serum samples were analysed for asparaginase activity and data analysis was done using nonlinear mixed effects modelling (NONMEM Vers. VI, Globomax, Hanouet, MD, USA). Different linear and nonlinear models were tested. The best model applicable to all dosing groups was a one-compartmental model with clearance (Cl) increasing with time according to the formula: Cl=Cl_i * e ^{(0·0793 * t )} where Cl_i = initial clearance and t  = time after dose. The parameters found were: volume of distribution ( V ) 1·02 ± 26% l/m², Cl_i 59·9 ± 59% ml/d per m² (mean ± interindividual variability). Interoccasion variability was substantial with 0·183 l/m² for V and 44·7 ml/d per m² for Cl, respectively. A subgroup of the patients showed a high clearance, probably due to the development of inactivating antibodies. This is the first model able to predict the activity-time course of PEG-asparaginase at different dosing levels and can therefore be used for developing new dosing regimens.