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A Semi-Mechanistic Population Pharmacokinetic/Pharmacodynamic Model of Bortezomib in Pediatric Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia

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Abstract

Introduction

The pharmacokinetics (PK) of the 20S proteasome inhibitor bortezomib are characterized by a large volume of distribution and a rapid decline in plasma concentrations within the first hour after administration. An increase in exposure was observed in the second week of treatment, which has previously been explained by extensive binding of bortezomib to proteasome in erythrocytes and peripheral tissues. We characterized the nonlinear population PK and pharmacodynamics (PD) of bortezomib in children with acute lymphoblastic leukemia.

Methods

Overall, 323 samples from 28 patients were available from a pediatric clinical study investigating bortezomib at an intravenous dose of 1.3 mg/m2 twice weekly (Dutch Trial Registry number 1881/ITCC021). A semi-physiological PK model for bortezomib was first developed; the PK were linked to the decrease in 20S proteasome activity in the final PK/PD model.

Results

The plasma PK data were adequately described using a two-compartment model with linear elimination. Increased concentrations were observed in week 2 compared with week 1, which was described using a Langmuir binding model. The decrease in 20S proteasome activity was best described by a direct effect model with a sigmoidal maximal inhibitory effect, representing the relationship between plasma concentrations and effect. The maximal inhibitory effect was 0.696 pmol AMC/s/mg protein (95% confidence interval 0.664–0.728) after administration.

Conclusion

The semi-physiological model adequately described the nonlinear PK and PD of bortezomib in plasma. This model can be used to further optimize dosing of bortezomib.

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Acknowledgements

The authors thank the investigators, research staff, and patients for their participation in this study.

Author information

Authors and Affiliations

  1. Department of Pharmacy and Pharmacology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Julie M. Janssen, T. P. C. Dorlo, J. H. Beijnen & A. D. R. Huitema

  2. Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands

    D. Niewerth & G. J. L. Kaspers

  3. Department of Clinical Pharmacology and Pharmacy, VU University Medical Center, Amsterdam, The Netherlands

    A. J. Wilhelm

  4. Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands

    C. M. Zwaan & G. J. L. Kaspers

  5. Department of Pediatric Oncology/Hematology, Erasmus-MC Sophia Children’s Hospital, Rotterdam, The Netherlands

    C. M. Zwaan

  6. Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands

    J. H. Beijnen

  7. Department of Pediatric Hematology and Oncology, St. Anna Children’s Hospital, Vienna, Austria

    A. Attarbaschi

  8. Department of Pediatrics and Adolescent Medicine, Medical University Vienna, Vienna, Austria

    A. Attarbaschi

  9. Department of Pediatric Hematology, Hopital Saint Louis, Paris, France

    A. Baruchel

  10. Università degli Studi di Torino, Turin, Italy

    F. Fagioli

  11. Department of Pediatrics, University Hospital Frankfurt, Frankfurt am Main, Germany

    T. Klingebiel

  12. Department of Pediatrics, Ghent University Hospital, Ghent, Belgium

    B. De Moerloose

  13. Ospedale Pediatrico Bambino Gesù, Rome, Italy

    G. Palumbo

  14. Department of Pediatric Oncology/Hematology, Charité Universitätsmedizin, Berlin, Germany

    A. von Stackelberg

  15. Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands

    A. D. R. Huitema

  16. ITCC Consortium, Paris, France

    C. M. Zwaan & A. Baruchel

Authors
  1. Julie M. Janssen
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  2. T. P. C. Dorlo
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  3. D. Niewerth
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  4. A. J. Wilhelm
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  5. C. M. Zwaan
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  6. J. H. Beijnen
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  7. A. Attarbaschi
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  8. A. Baruchel
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  9. F. Fagioli
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  10. T. Klingebiel
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  11. B. De Moerloose
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  12. G. Palumbo
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  13. A. von Stackelberg
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  14. G. J. L. Kaspers
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  15. A. D. R. Huitema
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Corresponding author

Correspondence to Julie M. Janssen.

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Funding

This clinical study was supported by the Dutch Foundation Children Cancer-Free (clinical research support) and by Janssen Pharmaceuticals (clinical research support and free drug).

Conflict of interest

A. Baruchel has declared links of interest with Amgen, Celgene, Jazz, Novartis, Servier, and Shire. J. M. Janssen, T. P. C. Dorlo, D. Niewerth, A. J. Wilhelm, C. M. Zwaan, J. H. Beijnen, A. Attarbaschi, F. Fagioli, T. Klingebiel, B. De Moerloose, G. Palumbo, A. von Stackelberg, G. J. L. Kaspers, and A. D. R. Huitema have no conflicts of interest to declare, other than the funding mentioned previously.

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Janssen, J.M., Dorlo, T.P.C., Niewerth, D. et al. A Semi-Mechanistic Population Pharmacokinetic/Pharmacodynamic Model of Bortezomib in Pediatric Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia. Clin Pharmacokinet 59, 207–216 (2020). https://doi.org/10.1007/s40262-019-00803-y

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  • DOI: https://doi.org/10.1007/s40262-019-00803-y

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