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Pharmacometric Applications and Challenges in the Development of Therapeutic Antibodies in Immuno-Oncology

  • Pharmacometrics (A Chakraborty, Section Editor)
  • Published:
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Abstract

Purpose of Review

Monoclonal antibodies targeting key checkpoints in immune stimulatory pathways have over the last years become the mainstay of cancer immuno-therapy. This article provides a brief review of the application and key impact of pharmacometrics and quantitative clinical pharmacology approaches in the development of these novel biologics.

Recent Findings

The clinical development and selection of optimal dosing regimens for monoclonal antibodies used in immuno-oncology has been facilitated by an extensive application of pharmacometric approaches to characterize the exposure-response relationship for major efficacy and safety endpoints. These analysis techniques were applied for the anti-CTLA-4 antibody ipilimumab, as well as the anti-PD1/PD-L1 antibodies nivolumab, pembrolizumab, avelumab, atezolizumab, and durvalumab. The utilization of quantitative clinical pharmacology, including model-based analyses, did not only support the identification of efficacious doses with acceptable safety limits but was also able to address complicating challenges such as time- and response-dependent changes in antibody clearance as observed for most compounds.

Summary

A widespread and systematic application of pharmacometric approaches has provided key aspects in elucidating, interpreting, and integrating preclinical, biochemical, and clinical data in support of the development of safe and efficacious dosing regimens of monoclonal antibodies used in immuno-oncology, thereby facilitating the clinical use of this promising new class of biologics in cancer patients with unmet medical needs.

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Acknowledgements

This work was partially supported by the National Cancer Institute of the National Institutes of Health under grant R01CA193609. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Clinical Pharmacology and Pharmacometrics, Bristol-Myers Squibb, Shanghai, China

    Lei Diao

  2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Avenue, Room 435, Memphis, TN, 38163, USA

    Bernd Meibohm

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  1. Lei Diao
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Correspondence to Bernd Meibohm.

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Conflict of Interests

LD is an employee of Bristol-Myers Squibb, the manufacturer of nivolumab and ipilimumab.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Pharmacometrics

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Diao, L., Meibohm, B. Pharmacometric Applications and Challenges in the Development of Therapeutic Antibodies in Immuno-Oncology. Curr Pharmacol Rep 4, 285–291 (2018). https://doi.org/10.1007/s40495-018-0142-5

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  • DOI: https://doi.org/10.1007/s40495-018-0142-5

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