Clinical Pharmacology Considerations for the Development of Immune Checkpoint Inhibitors. (15th September 2017)

• Record Type: Journal Article
• Authors: Sheng, Jennifer; Srivastava, Shivani; Sanghavi, Kinjal; Lu, Zheng; Schmidt, Brian J.; Bello, Akintunde; Gupta, Manish
• Other Names: Lee Lucy guestEditor.; Lewis Lionel D. guestEditor.
• Is Part Of: Journal of clinical pharmacology. Volume 57(2017)Supplement 10
• Page Start: S26
• Page End: S42
• Publication Date: 2017-09-15
• Subjects: immunopharmacology -- oncology -- clinical pharmacology -- clinical trials -- pharmacology -- immunotherapy -- checkpoint inhibitors; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Pharmacology, Clinical -- Periodicals; 615.1
• DOI: 10.1002/jcph.990
• Languages: English
• ISSNs: 0091-2700

Abstract

Abstract: Immuno‐oncology works through activation of the patient's immune system against cancer, with several advantages over other treatment approaches, including cytotoxic agents and molecular‐targeted therapies. The most notable feature of immuno‐oncology treatments is the nature of the patient responses achieved, which can be more durable and sustained than with other modalities. Increased understanding of immune system complexity has provided a number of opportunities to advance several strategies for the development of immuno‐oncology therapies. This review outlines the clinical pharmacology characteristics and development challenges for the 6 approved immunomodulatory monoclonal antibodies that target 2 immune checkpoint pathways: ipilimumab (an anti–cytotoxic T‐lymphocyte antigen‐4 antibody) and, more recently, nivolumab and pembrolizumab (both anti–programmed death‐1 antibodies) and atezolizumab, avelumab, and durvalumab (all anti–programmed death ligand‐1 antibodies). These agents have revealed much about the clinical pharmacology features of immune checkpoint inhibitors as a class, as well as the pharmacometric approaches used to support their clinical development and regulatory approval. The development experiences with these pioneering immuno‐oncology agents are likely to serve as useful guides in the discovery, progression, and approval of future drugs or combination of drugs in this class. This review includes summaries of the pharmacokinetics and exposure–response of the immune checkpoint inhibitors approved to date, as well as an overview of some quantitative systems pharmacology approaches. The ability of immuno‐oncology to meet its full potential will depend on overcoming development challenges, including the need for clear strategies to determine optimal dose and scheduling for monotherapy as well as combination approaches.