title: A population pharmacokinetic model for pegylated-asparaginase in children.
abstract: 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/m(2) 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/m(2), Cl(i) 59.9 +/- 59% ml/d per m(2) (mean +/- interindividual variability). Interoccasion variability was substantial with 0.183 l/m(2) for V and 44.7 ml/d per m(2) 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.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie - Klinische Pharmazie-, Westfälische Wilhelms-Universität Münster, Germany. georg.hempel@uni-muenster.de
authors.forename: Georg
authors.initials: G
authors.lastname: Hempel
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Müller
authors.forename: Claudia
authors.initials: C
authors.lastname: Lanvers-Kaminsky
authors.forename: Gudrun
authors.initials: G
authors.lastname: Würthwein
authors.forename: Antje
authors.initials: A
authors.lastname: Hoppe
authors.forename: Joachim
authors.initials: J
authors.lastname: Boos
mesh_terms: D000375:Aging / Q000097:blood; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood*; D001215:Asparaginase / Q000008:administration & dosage / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000097:blood*; D008297:Male; D008954:Models, Biological; D011092:Polyethylene Glycols / Q000008:administration & dosage; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood*; D012189:Retrospective Studies
chemical_list: D000970:Antineoplastic Agents; D011092:Polyethylene Glycols; C042705:pegaspargase; D001215:Asparaginase