605.

MOLECULAR PHARMACOLOGY, DRUG RESISTANCE -

LYMPHOID AND OTHER DISEASES: POSTER I | DECEMBER 03, 2015

Population Pharmacokinetics of Erwinia

Asparaginase in Pediatric ALL Patients
*,1 *,2 3
Sebastiaan D.T. Sassen , PharmD, Ron A.A. Mathôt , PharmD, PhD, Rob Pieters , MD PhD,
*,4 5 *,6
Valerie de Haas , MD PhD, Gertjan JL Kaspers , MD PhD, Cor van den Bos , MDPhD, Wim
*,7 8 9
JE Tissing , MD PhD, Maroeska D.W.M. te Loo , MD PhD, Marc B Bierings , MDPhD, Wouter
*,10 11 12
J.W. Kollen , MD PhD, Christian M. Zwaan , MD PhD, Inge M. van der Sluis , MD PhD
1
Pediatric Oncology, Erasmus MC - Sophia Children's Hospital, Rotterdam, Netherlands
2
Clinical Pharmacology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
3
Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands
4
Dutch Childhood Oncology Group (DCOG), The Hague, Netherlands
5
Pediatric Hematology Oncology, VU University Medical Center, Amsterdam, Netherlands
6
Department of Pediatric Oncology, Academic Medical Center, Amsterdam, Netherlands
7
Department of Paediatric Oncology, University Medical Center Groningen, Groningen, Netherlands
8
Pediatric Hemato-Oncology, UMCN St Radboud, Nijmegen, Netherlands
9
Department of Hematology and Immunology, Wilhelmina Children's Hospital, Utrecht, Netherlands
10
Department of Pediatric Immunology, Hemato-Oncology and Stem Cell
Transplantation, Leiden University Medical Center, Leiden, Netherlands
11
Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, Netherlands
12
Department of Pediatric Oncology/ Hematology, Erasmus MC - Sophia Children's Hospital, Rotterdam, Netherlands

Blood (2015) 126 (23) : 1281.

http://doi.org/10.1182/blood.V126.23.1281.1281

Abstract

Asparaginase is an important component in the treatment of pediatric acute lymphoblastic leukemia

(ALL). Erwinia asparaginase is used in patients who develop hypersensitivity to the E. coli derived
asparaginase (native asparaginase or PEGasparaginase). Little is known about the pharmacokinetics
(PK) of Erwinia asparaginase, especially after intravenous administration. A 100-fold difference in
Erwinia asparaginase serum trough levels between patients has been observed during therapeutic drug
monitoring (TDM). Currently, in DCOG ALL-protocols dose alterations of asparaginase and erwinase are
based on TDM, with the aim to keep the trough asparaginase activity above the 100 IU/L threshold. No
formal guidelines for increasing or decreasing the dose are available, and dose-adaptations are based on
empirical knowledge. With a PK model, individual dose requirements can be estimated based on their PK
parameters like clearance. The final aim is to avoid under-exposure and relapse, or over-exposure which
may induce side-effects and results in unnecessary costs. However the upper limit of the therapeutic
window that causes toxicity is not known.

Aims

The aim of this retrospective study was to describe the population PK of Erwinia asparaginase to gather
insight in the inter-individual and intra-individual variability, and which co-variates influence exposure.
Availability of a population PK model will allow the calculation of a starting dose and subsequent dosing in
TDM-setting in the future.

Methods

A total of 714 evaluable blood samples were collected from 51 children with ALL who received
intravenous Erwinia asparaginase as a substitute for E. coli or PEG asparaginase, when treated
according to the DCOG ALL-10 or 11 protocol. Patients (32 males and 19 females), had a median age
2
of 6 years (range 1-17), median weight of 25 kg (12-99) and median BSA of 0.92 m (0.53-2.22). The
median number of samples per patient was 11 (2 - 43). Samples were taken approximately 48 (52.2%)
and 72 (36.8%) hours after administration. In addition, samples within 5h (2.4%), between 5-40h (1.3%)
and between 80-120h (7.3%) after administration were available. The Erwinia starting dose was 20,000
2
IU/m /3x per week, and was given IV over 1 hour, and was later adapted based on TDM to 5,000-50,400
2
IU/m twice (54.2%) or thrice (45.8%) weekly. A population pharmacokinetic model was developed using
nonlinear mixed-effects modeling (NONMEM 7.2; pirana 2.7.1; Xpose4). Monte Carlo simulations were
performed with different doses and stratification for body weight (n=5000 per dose per weight).

Results

The concentration versus time profiles were best described with a 2-compartment model with allometric
scaling (weight). The parameter estimates were: Cl 0.439 L/h/70kg, V1 (central compartment) 3.22
L/70kg, intercompartimental clearance 0.149 L/h/70kg and V2 (peripheral compartment) 1.14 L/70kg. The
interindividual variability of clearance was 32.6%. There was an interoccasion variability of 12.7% based
on monthly intervals. Clearance in the first month of treatment was 14% higher compared to the other
months (p<0.01). Additional incorporation of age, DCOG protocol (ALL-10 or 11), treatment center, sex
and BSA did not improve the model significantly.

Based on the simulations, patients with a lower body weight appeared to require higher starting doses
2
to achieve sufficient erwinase levels after 48 hours. With the current starting dose of 20,000 IU/m , circa
75% of the patients >50kg would have levels >100 IU/L after 48h. For patients between 20-50 kg the
2
dose starting dose should be 25,000 IU/m in order to achieve levels >100 IU/L at 48h in 75% of the
2
patients. In our study, of 36 patients with evaluable starting doses (dosed 20,000 IU/m and with an
available 48h sample), 38.7% (from a total of 31 patients <50 kg) and 20% (from a total of 5 patients

≥50kg group) had 48h trough levels below 100 IU/L.

Conclusions

A population PK model was developed for Erwinia asparaginase in pediatric ALL patients. Depending on
the weight of the patients the currently used starting dose of 20,000 IU/m2 may need to be adjusted to
produce similar trough asparaginase activity, which needs to be confirmed prospectively. The PK model
can be used for TDM to calculate dose adjustments in individual patients based on single PK samples,
which might result in better dose-predictions than used in current practice.

Disclosures
Pieters: Eusa Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or
advisory committees. Kaspers: Celgene: Consultancy; Boehringer Ingelheim: Consultancy; Galen
Pharmaceuticals: Consultancy. van der Sluis: Eusa Pharma: Consultancy, Membership on an entity's
Board of Directors or advisory committees, Research Funding.

Author notes
*Asterisk with author names denotes non-ASH members.

This icon denotes a clinically relevant abstract

© 2015 by the American Society of Hematology