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Role of Clinical Pharmacodynamics Studies in the Era of Precision Medicines Against Cancer

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Drug Discovery and Evaluation: Methods in Clinical Pharmacology

Abstract

Pharmacodynamics (PD) has been integral to the design of rational drug dosing regimens. Detailed PD studies during both the preclinical and clinical stages of the drug development process can also contribute to lead optimization or the selection of the optimal “best-in-class” compound, improve clinical potency estimates and help predict the drug exposure needed to achieve meaningful clinical responses. There has been a substantial and continued increase in the number of clinical oncology trials with integrated PD studies since 2002. Notably, a significant portion of all interventional clinical trials with PD components are initiated for evaluation of oncology drugs. PD studies frequently play a pivotal role in determining the initial dose level for first-in-human clinical studies of immunooncology drugs. The integration of PD data into the dose safety modeling in early oncology studies may provide accurate predictions of the dose-effect relationships by advancing the understanding of target engagement as well as exposure response and therefore has the potential to improve the decision making regarding the optimal dose and schedules as well as risk-benefit assessments for later stages in clinical development. PD studies also have the potential to provide early clinical proof of concept when drugs with complementary activity profiles are combined in cancer therapy. In recent years, population pharmacokinetics–pharmacodynamics (PK-PD) modeling has become a key tool towards streamlining and optimizing oncologic drug development through early understanding, identification and quantification of various dose–response relationships in the context of other patient characteristics as well as risk-benefit of different dosing schedules. Finally, a new and exciting strategy known as “Quantitative Systems Pharmacology” is emerging that advances systems level, multiscale models for disease progression and treatment to better characterize the hierarchical, non-linear, dynamic responses at the network level of drug action that may affect both efficacy and toxicity in clinical settings.

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Authors and Affiliations

  1. AresMIT Biomedical Computational Strategies (ABCS), Minneapolis, MN, USA

    Fatih M. Uckun & Sanjive Qazi

  2. Ares Pharmaceuticals, St. Paul, MN, USA

    Fatih M. Uckun & Sanjive Qazi

  3. Bioinformatics Program, Gustavus Adolphus College, St. Peter, MN, USA

    Sanjive Qazi

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  1. Fatih M. Uckun
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Correspondence to Fatih M. Uckun .

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  1. CorDynamics , Dieburg, Germany

    Franz J. Hock

  2. CorDynamics , Chicago, IL, USA

    Michael R. Gralinski

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Uckun, F.M., Qazi, S. (2019). Role of Clinical Pharmacodynamics Studies in the Era of Precision Medicines Against Cancer. In: Hock, F., Gralinski, M. (eds) Drug Discovery and Evaluation: Methods in Clinical Pharmacology. Springer, Cham. https://doi.org/10.1007/978-3-319-56637-5_37-1

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