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Pharmacokinetics of PEGasparaginase in Infants with Acute Lymphoblastic Leukemia

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Abstract

Background

PEGasparaginase is known to be a critical drug for treating pediatric acute lymphoblastic leukemia (ALL), however, there is insufficient evidence to determine the optimal dose for infants who are less than one year of age at diagnosis. This international study was conducted to identify the pharmacokinetics of PEGasparaginase in infants with newly diagnosed ALL and gather insight into the clearance and dosing of this population.

Methods

Infants with ALL who received treatment with PEGasparaginase were included in our population pharmacokinetic assessment employing non-linear mixed effects modelling (NONMEM).

Results

68 infants with ALL, with a total of 388 asparaginase activity samples, were included. PEGasparaginase doses ranging from 400 to 3,663 IU/m2 were administered either intravenously or intramuscularly. A one-compartment model with time-dependent clearance, modeled using a transit model, provided the best fit to the data. Body weight was significantly correlated with clearance and volume of distribution. The final model estimated a half-life of 11.7 days just after administration, which decreased to 1.8 days 14 days after administration. Clearance was 19.5% lower during the post-induction treatment phase compared to induction.

Conclusion

The pharmacokinetics of PEGasparaginase in infants diagnosed under one year of age with ALL is comparable to that of older children (1–18 years). We recommend a PEGasparaginase dosing at 1,500 IU/m2 for infants without dose adaptations according to age, and implementing therapeutic drug monitoring as standard practice.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

Author LB would like to thank Nienke Wieringa for collecting PK data collection.

Author VM would like to thank Tim Lammens and the Asparaginase therapeutic drug monitoring laboratorium for performing the PK analyses and all involved hospitals for data collection.

CR wishes to thank the Comitato ML Verga (Monza, Italy), the Association “Insieme ad Andrea si può” ONLUS (Jerago con Orago, Varese, Italy), the MBBM Foundation (Monza, Italy), the Istituto Mario Negri for Pharmacological Researches (Milano, Italy) and the Italian Association of Pediatric Hematology and Oncology (AIEOP) for the support provided to his researches on asparaginase preparations.

Funding

Author VM: This work was supported by the Cancer Plan Action 29 from the Belgian Federal Public Service of Health; the Flemisch League Against Cancer, vzw Kinderkankerfonds and the Clinical Research Fund of the Ghent University Hospital.

Author information

Author notes

  1. Alwin D. R. Huitema and Inge M. van der Sluis are shared last author.

Authors and Affiliations

  1. Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, Netherlands

    Leiah J. Brigitha, Rob Pieters, Alwin D. R. Huitema & Inge M. van der Sluis

  2. Pediatric Oncology and Hematology, Erasmus MC–Sophia Children’s Hospital, Dr. Molewaterplein 40, 3015 GD, Rotterdam, Netherlands

    Leiah J. Brigitha

  3. Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent University, Corneel Heymanslaan 10, 9000, Ghent, Belgium

    Veerle Mondelaers

  4. Department of Bioinformatics and Computational Biology, the University of Texas MD Anderson Cancer Center, Houston, USA

    Yiwei Liu

  5. Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Palle Juul-Jensens Blvd. 99, 8200, Aarhus, Denmark

    Birgitte K. Albertsen

  6. Department of Pediatrics, Medical University of Lodz, Oncology & Hematology, 91-738, Lodz, Poland

    Beata Zalewska-Szewczyk

  7. Department of Pediatrics, University of Milano-Bicocca, Piazza Dell’Ateneo Nuovo, 1, Milano, Italy

    Carmelo Rizzari

  8. Fondazione IRCCS San Gerardo Dei Tintori, Via G.B. Pergolesi 33, Monza, Italy

    Carmelo Rizzari

  9. Department of Clinical Haematology, Oncology, Blood and Marrow Transplantation, Perth Children’s Hospital, Perth, Australia

    Rishi S. Kotecha

  10. Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, Australia

    Rishi S. Kotecha

  11. Curtin Medical School, Curtin University, Perth, Australia

    Rishi S. Kotecha

  12. Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX, Utrecht, the Netherlands

    Alwin D. R. Huitema

  13. Department of Pharmacy & Pharmacology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands

    Alwin D. R. Huitema

Authors
  1. Leiah J. Brigitha
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  2. Veerle Mondelaers
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  3. Yiwei Liu
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  4. Birgitte K. Albertsen
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  5. Beata Zalewska-Szewczyk
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  6. Carmelo Rizzari
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  7. Rishi S. Kotecha
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  8. Rob Pieters
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  9. Alwin D. R. Huitema
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  10. Inge M. van der Sluis
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Contributions

LJB, RP, and IvdS were responsible for protocol development and implementation of the study. LJB, VM, YL, BKA, BZS, CR, RSK, RP, and IvdS were responsible for enrolling patients. Acquisition of the data was performed by all authors. Population PK modelling was performed by LJB, AH supervised this work. The first draft of the manuscript was written by LJB, and all the authors commented on previous versions of the manuscript. All the authors read and approved the final manuscript.

Corresponding author

Correspondence to Inge M. van der Sluis.

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Conflict of Interest

LJB: Speaker fee from Servier and Clinigen.

VM: Participation in advisory boards of Servier and Clinigen, and travel grants from Servier and Jazz Pharmaceuticals.

BKA: Participation in advisory boards of Jazz Pharmaceuticals.

RP: Participation in advisory boards of Servier, Jazz Pharmaceuticals and Clinigen. And speaker fee from Servier and Clinigen.

IvdS: Participation in advisory boards of Servier, Jazz Pharmaceuticals and Clinigen. And speaker fee from Servier and Clinigen.

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Brigitha, L.J., Mondelaers, V., Liu, Y. et al. Pharmacokinetics of PEGasparaginase in Infants with Acute Lymphoblastic Leukemia. Pharm Res 41, 711–720 (2024). https://doi.org/10.1007/s11095-024-03693-3

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