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Setting the Dose of Checkpoint Inhibitors: The Role of Clinical Pharmacology

  • Etienne ChatelutEmail author
  • Félicien Le Louedec
  • Gérard Milano
Review Article

Abstract

Cancer immunotherapy is based on checkpoint inhibitors (CPIs) that significantly improve the clinical outcome of several malignant diseases. These inhibitors are monoclonal antibodies (mAbs) directed at cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), or programmed death-ligand 1 (PD-L1), sharing most of the clinical pharmacokinetic characteristics of mAb targeted therapies, all of which differ from those of cytotoxics and small molecules. Establishing the labeled dose of mAbs, and particularly of the CPIs, represents a true challenge. This review therefore examines the main criteria used for dose selection, along with their limits. The relationships between CPI pharmacokinetic parameters and treatment outcome (efficacy and/or toxicity) differ somewhat among the various drugs, but general features can be identified. Nevertheless, the interpretation of these relationships remains quite controversial. A first interpretation asserts that inter-individual pharmacokinetic variability in clearance has an impact on outcome and should be taken into consideration for dosing individualization. The second considers that higher clearance values observed in some patients result from characteristics associated with poor predictive factors of efficacy. Finally, the schedule, and particularly its frequency of administration, merits rethinking.

Notes

Acknowledgements

The authors would like to thank Dr Gail Taillefer, a native English-speaking medical writer (Professor emeritus of English), for her language and editorial support.

Funding

No funding was received that is directly relevant to the content of this review.

Compliance with Ethical Standards

Conflict of interest

Etienne Chatelut, Félicien Le Louedec, and Gérard Milano declare that they have no conflict of interests related to the content of this review.

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Institut Claudius-Regaud, IUCT-Oncopole, and CRCTUniversité de Toulouse, InsermToulouse Cedex 9France
  2. 2.Oncopharmacology UnitCentre Antoine LacassagneNiceFrance

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