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Ferrata Storti Foundation
Haematologica 2021 Volume 106(5):1254-1261
Acute Lymphoblastic Leukemia
Individualized dosing guidelines for PEGasparaginase and factors influencing the clearance: a population pharmacokinetic model
Robin Q.H. Kloos,1 Ron Mathôt,2 Rob Pieters3 and Inge M. van der Sluis1,3
1Department of Pediatric Oncology and Hematology, Sophia Children’s Hospital – Erasmus MC, Rotterdam; 2Department of Hospital Pharmacy, Amsterdam University Medical Center, University of Amsterdam, Amsterdam and 3Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
ABSTRACT
Considerable inter- and intra-patient variability exist in serum activ- ity levels of PEGasparaginase, essential for pediatric acute lym- phoblastic leukemia (ALL) treatment. A population pharmacoki- netic (popPK) model was developed, identifying patient characteristics that explain these variabilities. Patients (n=92) were treated according to the Dutch Childhood Oncology Group (DCOG) ALL-11 protocol, using therapeutic drug monitoring to individualize PEGasparaginase doses. Non-linear mixed effects modeling (NONMEM) was used to analyze popPK evaluating several covariates. The final model was validated using an independent database (n=28). Guidelines for starting doses and dose adjustments were developed. A one-compartment model with time- dependent clearance was adequately described in popPK. Normalization of clearance and volume of distribution by body surface area reduced inter-individual variability. Clearance was 0.084 L/day/m2 for 12.7 days, increasing by 0.082 L/day/m2/day thereafter. Clearance was 38% higher during an infection, and 11-19% higher during induction treatment than during intensification and maintenance (P<0.001). In order to target an asparaginase activity level of 100 IU/L, a loading dose of 800 IU/m2 (induction) and 600 IU/m2 (intensification) is advised. In conclusion, vari- ability of PEGasparaginase activity levels can be explained by body sur- face area, the treatment phase and the occurrence of an infection. With this popPK model, PEGasparaginase treatment can be individualized fur- ther, taking into account the covariates and the dosing guidelines provid- ed. (clinicaltrials gov. Identifier [CCMO register]: NL50250.078.14).
Introduction
Asparaginase plays an important role in the treatment of pediatric acute lym- phoblastic leukemia (ALL). The drug converts asparagine in aspartic acid and ammonia, resulting in apoptosis of the leukemic cells, as these cells highly depend on extracellular asparagine pools for protein synthesis.1-3 An asparaginase activity level of >100 IU/L is considered to be sufficient for complete asparagine depletion.4-10 Currently, different formulations of asparaginase derived from Erwinia chrysanthemi or Escherichia coli (E. coli) are available in clinical practice, all with different pharma- cokinetic (PK) properties.11,12 One of these formulations is the polyethylene glycol (PEG) conjugated form of E. coli asparaginase, also known as PEGasparaginase, which has several advantages compared to the native E.coli asparaginase. First, the risk of developing a neutralizing hypersensitivity reaction to asparaginase is reduced when using PEGasparaginase.13-15 Second, PEGasparaginase can be adminis- tered less frequently than other asparaginase formulations because of its relatively low clearance (CL).16,17 Therefore, PEGasparaginase is currently used as a first-line formulation in most developed countries. However, considerable inter- and intra- patient variability of PEGasparaginase levels has been observed and it is, therefore, difficult to determine the right dose for an individual patient.17,18 Currently, asparag- inase therapy in Dutch pediatric patients with ALL, treated according to the Dutch Childhood Oncology Group (DCOG) ALL-11 protocol, is individualized with ther-
Correspondence:
INGE M. VAN DER SLUIS
i.m.vandersluis@prinsesmaximacentrum.nl
Received: November 4, 2019. Accepted: April 9, 2020. Pre-published: April 23, 2020.
https://doi.org/10.3324/haematol.2019.242289
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