A population pharmacokinetic model for pegylated‐asparaginase in children

Abstract

Summary 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=Cli *e(0·0793 *t) where Cli = initial clearance and t = time after dose. The parameters found were: volume of distribution (V) 1·02 ± 26% l/m2, Cli 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.

Impact of anti-PEG IgM antibodies on the pharmacokinetics of pegylated asparaginase preparations in mice

“…The well-known PK profile (increased elimination with time) of pegaspargase was confirmed in this study (Panetta et al, 2009;Hempel et al, 2010;Borghorst et al, 2014) (Fig. 4).…”

Population Pharmacokinetics of NativeEscherichia ColiAsparaginase

“…The GOF plot for the population predictions versus the observed ASNase activity levels (Figure 4) as well as the individual predictions versus [8,9]. To our knowledge, the presented model is the first reported PopPK model for ASNase medac TM .…”

“…On the contrary, the PE-Gylated preparation is best described by a nonlinear elimination. Population pharmacokinetic (PopPK) analyses proposed a 1-compartment model with either timedependent clearance or Michaelis-Menten elimination [8,9]. A PopPK model for the native E. coli ASNase preparation is still lacking.…”

Discussion about Several Potential Drawbacks of PEGylated Therapeutic Proteins

“…But the phenomenon of increased drug clearance has been observed in a subgroup of pediatric patients treated for ALL without any clinical evidence of an allergic reaction. 54,55) Armstrong et al 56) showed that the presence of anti-PEG was very closely associated with rapid clearance of PEG-ASNase.…”