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

Abstract

Monoclonal antibodies targeting key checkpoints in immune stimulatory pathways have over the last years become the mainstay of cancer immunotherapy. 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. The clinical development and selection of optimal dosing regimens for monoclonal antibodies used in immune-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. 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.