A population pharmacokinetic model for pegylated-asparaginase in children

作者：Hempel Georg^*; Mueller Hans Joachim; Lanvers Kaminsky Claudia; Wuerthwein Gudrun; Hoppe Antje; Boos Joachim

来源：British Journal of Haematology, 2010, 148(1): 119-125.

DOI：10.1111/j.1365-2141.2009.07923.x

• pharmacokinetics
• paediatric oncology
• pharmacology
• acute leukaemia

P>We analysed 1221 serum activity measurements in 168 children from the Berlin-Frankfurt-Munster acute lymphoblastic leukaemia studies, ALL-BFM (Berlin-Frankfurt-Munster) 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 center dot 0793 *t) where Cl(i) = initial clearance and t = time after dose. The parameters found were: volume of distribution (V) 1 center dot 02 +/- 26% l/m2, Cl(i) 59 center dot 9 +/- 59% ml/d per m2 (mean +/- interindividual variability). Interoccasion variability was substantial with 0 center dot 183 l/m2 for V and 44 center dot 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.

• 出版日期2010-1