Pharmacokinetic/pharmacodynamic relationship of therapeutic monoclonal antibodies used in oncology: Part 2, immune checkpoint inhibitor antibodies. (March 2020)

• Record Type: Journal Article
• Authors: Desnoyer, Aude; Broutin, Sophie; Delahousse, Julia; Maritaz, Christophe; Blondel, Louis; Mir, Olivier; Chaput, Nathalie; Paci, Angelo
• Is Part Of: European journal of cancer. Volume 128(2020)
• Page Start: 119
• Page End: 128
• Publication Date: 2020-03
• Subjects: Checkpoint inhibitors -- Pharmacokinetics -- Pharmacodynamic properties -- Therapeutic drug monitoring -- Cancer; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2020.01.003
• Languages: English
• ISSNs: 0959-8049

Abstract

Abstract: Immune checkpoint inhibitors are monoclonal antibodies (mAbs) directed against negative immunologic regulators that are used to restore the immune response against cancer. Approved drugs include anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), anti-programmed cell death 1 (PD-1) and anti-programmed cell death-ligand 1 (PD-L1) antibodies exhibiting pharmacokinetic (PK) characteristics typical of mAbs. Most factors such as age, sex, ethnicity, tumour burden, performance status and immunogenicity, but not body weight, do not seem to affect drug clearance clinically. However, an exposure-response relation has been described for both the efficacy and toxicity of anti-CTLA-4 and anti-PD-1 agents. The change in clearance over time is associated with overall response at least for nivolumab and pembrolizumab. Few PK/pharmacodynamic (PD) data are available for anti-PD-L1 mAbs, but time-varying clearance has been described for these drugs, and the high immunogenicity rate observed with atezolizumab may affect PK parameters and should be further studied. These data suggest the need for additional PK/PD studies. In this review, we summarise studies of the PKs of immune checkpoint inhibitors, exploring possible interactions with PD considerations. Highlights: A dose and exposure-response relation is evidenced for cytotoxic T-lymphocyte antigen 4. No dose-response relation is evidenced for anti-programmed cell death 1 (PD1) and anti-programmed cell death-ligand 1(PD-L1). Combined data suggest an exposure-response relations for these monoclonal antibodies. An association between time-varying clearance and patient response is evidenced for anti-PD1 and anti-PD-L1. Studies should be conducted to further understand the pharmacokinetic/pharmacodynamic relations of these drugs.