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Cost-Neutral Optimization of Pazopanib Exposure by Splitting Intake Moments: A Prospective Pharmacokinetic Study in Cancer Patients

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Abstract

Background and Objective

Pazopanib is an oral tyrosine kinase inhibitor used in the treatment of renal cell carcinoma and soft-tissue sarcoma. At the approved dose of 800 mg once daily (QD), 16–20% of patients are being underdosed and at risk of decreased efficacy. This study aimed to show whether splitting intake moments, as a cost-neutral alternative to a dose increase, leads to an increased exposure.

Methods

We performed a cross-over trial comparing the pharmacokinetics of pazopanib 800 mg QD with pazopanib 400 mg twice daily. Pharmacokinetic sampling was performed at steady-state for both dosing schedules.

Results

Nine evaluable patients were included. At the 800 mg QD dosing schedule, median minimum plasma concentration (Cmin), area under the concentration–time curve from 0 to 24 h (AUC0–24h), and maximum plasma concentration (Cmax) were 23.2 mg/L (interquartile range 18.5–27.6), 773 mg h/L (557–1009), and 40.6 mg/L (36.4–56.4) compared with 41.6 mg/L (30.5–55.8, p = 0.004), 942 mg h/L (885–1419, p = 0.027), and 50.2 mg/L (46.8–72.5, p = 0.074) at 400 mg twice daily. One patient experienced a grade 3 event (i.e., diarrhea).

Conclusions

This study demonstrates that splitting intake moments of pazopanib leads to a 79% increase in Cmin, with acceptable tolerability. Therefore, this new dosing schedule offers a cost-neutral opportunity to optimize treatment in patients with low exposure.

Clinical Trial Registration

NL6137 (http://www.trialregister.nl).

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Acknowledgements

We thank all patients for their participation in this study. We thank Dr. Huixin Yu for performing the simulations. In addition, we thank the study team for their contribution, in particular Else Meijer and Brigitte Dufourny. This work was presented in part at the 2019 American Society of Clinical Oncology Annual Meeting, Chicago, IL, USA (J Clin Oncol. 2019;37 Suppl.:abstract 3119).

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Authors and Affiliations

  1. Division of Medical Oncology, Department of Clinical Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Stefanie L. Groenland & Neeltje Steeghs

  2. Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

    Ruben A. G. van Eerden, Stijn L. W. Koolen & Ron H. J. Mathijssen

  3. Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands

    Remy B. Verheijen, Niels de Vries, Bas Thijssen, Hilde Rosing, Jos H. Beijnen & Alwin D. R. Huitema

  4. Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

    Jos H. Beijnen

  5. Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands

    Stijn L. W. Koolen

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

    Alwin D. R. Huitema

Authors
  1. Stefanie L. Groenland
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  2. Ruben A. G. van Eerden
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  3. Remy B. Verheijen
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  6. Hilde Rosing
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  7. Jos H. Beijnen
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  8. Stijn L. W. Koolen
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  9. Ron H. J. Mathijssen
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  10. Alwin D. R. Huitema
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  11. Neeltje Steeghs
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Consortia

The Dutch Pharmacology Oncology Group (DPOG)

Corresponding author

Correspondence to Stefanie L. Groenland.

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Funding

No funding has been received for the conduct of this study of the preparation of this article.

Conflict of interest

Remy B. Verheijen is currently an employee and shareholder of AstraZeneca, Cambridge, UK. Stijn L.W. Koolen and Ron H.J. Mathijssen received funding and speakers’ fees by Novartis on a topic not related to the current study. Jos H. Beijnen is a part-time employee, stock holder, and patent holder of Modra Pharmaceuticals (a spin-out company developing oral taxane formulations, not related to this study). Stefanie L. Groenland, Ruben A.G. van Eerden, Niels de Vries, Bas Thijssen, Hilde Rosing, Alwin D.R. Huitema, and Neeltje Steeghs have no conflicts of interest that are directly relevant to the content of this article.

Ethics approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee (Medical Ethics Committee of The Netherlands Cancer Institute-Antoni van Leeuwenhoek, reference number: METC17.482/N17PSI) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

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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Groenland, S.L., van Eerden, R.A.G., Verheijen, R.B. et al. Cost-Neutral Optimization of Pazopanib Exposure by Splitting Intake Moments: A Prospective Pharmacokinetic Study in Cancer Patients. Clin Pharmacokinet 59, 941–948 (2020). https://doi.org/10.1007/s40262-020-00863-5

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  • DOI: https://doi.org/10.1007/s40262-020-00863-5

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