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

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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.

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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.

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

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Authors and Affiliations

  1. Institut Claudius-Regaud, IUCT-Oncopole, and CRCT, Université de Toulouse, Inserm, 1, avenue Irène Joliot-Curie - IUCT-O, Toulouse Cedex 9, France

    Etienne Chatelut & Félicien Le Louedec

  2. Oncopharmacology Unit, Centre Antoine Lacassagne, Nice, France

    Gérard Milano

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  1. Etienne Chatelut
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  2. Félicien Le Louedec
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  3. Gérard Milano
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Correspondence to Etienne Chatelut.

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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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Chatelut, E., Le Louedec, F. & Milano, G. Setting the Dose of Checkpoint Inhibitors: The Role of Clinical Pharmacology. Clin Pharmacokinet 59, 287–296 (2020). https://doi.org/10.1007/s40262-019-00837-2

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