Population Pharmacokinetic of Native Escherichia Coli Asparaginase.

Native Escherichia Coli Asparaginase (ASNase) is an integral component in the therapy of acute lymphoblastic leukemia (ALL) and non-Hodgkin's Lymphoma (NHL). There is a great interindividual variability in treatment intensity in patients treated with the same dose of ASNase. Population pharmacokinetics (PopPK) provides the possibility to divide the overall variability of a population in an inter- and intraindividual element and to develop more precise dosing recommendations. Furthermore, pharmacokinetic parameters can be estimated as well as possible covariates that may influence the pharmacokinetics of the drug can be identified.

The model building dataset consisted of 16 patients (233 samples) receiving 5000 U/m² ASNase (Asparaginase Medac®) 8 times according to the DCOG-ALL 10 treatment protocol. Asparaginase activity was measured in a randomized clinical Phase 2 study comparing the pharmacokinetic and pharmacodynamic of a newly developed recombinant ASNase with that of the established ASNase (Asparaginase Medac®)[R. Pieters et al. Blood. 2008 Dec 15. 112(13):4832-8]. The PopPK-model was developed using NONMEM (version VI) with First Order Conditional Estimation (FOCE) method and INTERACTION option.

A linear 2-compartmental model with a combined proportional (0.9%) and additive (48.1U/l) error model described the data adequately. The pharmacokinetic parameters estimated were: Total systemic clearance 0.135 ± 12.8% l/h/70kg, volume of distribution of the central compartment 4.27 ± 13.1% l/70kg, volume of distribution in the peripheral compartment 0.83 ± 80.4% l/70kg and intercompartmental clearance 0.058 l/h/70kg (mean ± interindividual variability). Body weight was identified as the most important covariate. Validity of the model was verified by simulating different dosages of ASNase (2500U/m² and 10000U/m²) in induction and reinduction of the ALL-BFM treatment protocol. The median and mean ASNase activity was compared with published data [E. Ahlke et al. Br J Haematol. 1997 Mar. 96(4):675-81 and Boos et al. Eur J Cancer. 1996 Aug. 32A(9):1544-50]. Furthermore pharmacokinetic data obtained by a noncompartmental analysis [R. Pieters et al. Blood. 2008 Dec 15.112(13):4832-8] were compared with the pharmacokinetic data estimated by the PopPK model. Both procedures indicated on face validity of the PopPK model.

This PopPK analysis provides the first step in the development of a PopPK model for ASNase. Face validity of the PopPK model could be demonstrated and will be confirmed with an independent dataset.

Pieters:Medac GmbH: Research Funding. Kuehnel:Medac GmbH: Employment. Boos:Medac GmbH: Honoraria. Hempel:Medac GmbH: Honoraria.