Clinical Pharmacokinetics and Pharmacodynamics of Immune Checkpoint Inhibitors

• Published in: Clinical pharmacokinetics Vol. 58; no. 7; pp. 835 - 857
• Main Authors: Centanni, Maddalena, Moes, Dirk Jan A. R., Trocóniz, Iñaki F., Ciccolini, Joseph, van Hasselt, J. G. Coen
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.07.2019; Springer Nature B.V; Springer Verlag
• Subjects: Animals; Antibodies, Monoclonal - pharmacokinetics; Antibodies, Monoclonal - therapeutic use; Antineoplastic Agents, Immunological - pharmacokinetics; Antineoplastic Agents, Immunological - pharmacology; Antineoplastic Agents, Immunological - therapeutic use; Biomarkers; Cancer; Cancer therapies; Clinical outcomes; Clinical trials; Dose-Response Relationship, Drug; Dose-Response Relationship, Immunologic; Drug dosages; FDA approval; Human health and pathology; Humans; Immunoglobulins; Internal Medicine; Kidney cancer; Life Sciences; Medical prognosis; Medicine; Medicine & Public Health; Melanoma; Metastasis; Neoplasms - drug therapy; Oncology; Patients; Pharmacodynamics; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Prostate cancer; Regulatory approval; Review; Review Article; Systematic review; Treatment Outcome
• ISSN: 0312-5963; 1179-1926
• DOI: 10.1007/s40262-019-00748-2

Immune checkpoint inhibitors (ICIs) have demonstrated significant clinical impact in improving overall survival of several malignancies associated with poor outcomes; however, only 20–40% of patients will show long-lasting survival. Further clarification of factors related to treatment response can support improvements in clinical outcome and guide the development of novel immune checkpoint therapies. In this article, we have provided an overview of the pharmacokinetic (PK) aspects related to current ICIs, which include target-mediated drug disposition and time-varying drug clearance. In response to the variation in treatment exposure of ICIs and the significant healthcare costs associated with these agents, arguments for both dose individualization and generalization are provided. We address important issues related to the efficacy and safety, the pharmacodynamics (PD), of ICIs, including exposure–response relationships related to clinical outcome. The unique PK and PD aspects of ICIs give rise to issues of confounding and suboptimal surrogate endpoints that complicate interpretation of exposure–response analysis. Biomarkers to identify patients benefiting from treatment with ICIs have been brought forward. However, validated biomarkers to monitor treatment response are currently lacking.