Dose Recommendations for Recombinant Asparaginase in Children: A Population Pharmacokinetic Analysis

Swantje Völler (1) *, Uwe Pichlmeier (2), Gudrun Würthwein (1), Georg Hempel (1)

(1) Institute of pharmaceutical and medicinal Chemistry, Clinical Pharmacy, Westfälische Wilhelms-Universität Münster, Germany, (2) medac, Gesellschaft für klinische Spezialpräparate mbH, Hamburg, Germany, *current address: LACDR Leiden, Faculty of Science, Universiteit Leiden, The Netherlands

Swantje Völler

Poster: Drug/Disease modeling - Paediatrics

Objectives: The enzyme Asparaginase is used for remission induction and post-induction treatment in acute lymphoblastic leukemia. A new recombinant E.coli-Asparaginase (rASNase) was developed by medac GmbH (Wedel, Germany) and recently approved by the EMA. Bio analytical data originated from three clinical studies in children (EudraCT numbers: 2004-003785-16, 2006-003180-31, 2008-006300-27) was available for population pharmacokinetic (popPK) analysis.

Methods: A popPK model for rASNase was developed using NONMEM® 7.2 and a predefined step-by-step model building process. During treatment trough activity of rASNase should be maintained above 100 U/L to keep serum asparagine levels undectecable. Based on simulations of the popPK model, different dose adjustments were investigated for their ability to increase rASNase trough activities in those patients affected by low through activities.

Results: One hundred twenty-four children with previously untreated acute lymphatic leukaemia were included in the analysis. Model-building resulted in a two compartment model for rASNase (CL=0.154 L/h/70 kg, V1=4.24 L/70 kg, Q=0.801 L/h/70kg, V2=1.13 L/70 kg). Inter individual variability on CL (20.4%) and V1 (20.2%), intra-individual variability of the V1 (12.5%) and residual variability (proportional error 2.25%, additive error 34.7 U/L) were assessed. Allometric scaling with a fixed exponent of 0.75 on weight for CL and Q, and weight on V1 and V2 was used. Further covariates, e.g. liver function, kidney function, fibrinogen or antithrombin III did not influence the model. Simulations suggest that neither doubling the dose nor shortening the dose interval in patients with rASNase trough activities below 25 U/L are likely to result in activities above 100 U/L for the following administrations. For activities between 25 U/L and 50 U/L, it might be useful to reduce the dose interval from every 72h to every 48h. For activities between 50 U/L and 75 U/L, simulations suggest that doubling the dose is an alternative to reducing the dose interval. If the trough activity is between 75 U/L and 100 U/L (d), increasing the dose by 50% appears to be sufficient to reach trough activities above 100 U/L, associated with an acceptable increase in peak activities.

Conclusions: A popPK model describing the PK of rASNase in children was successfully developed and validated. The model can be used to aid dose finding in children affected trough activities below 100 U/L.