Pharmacokinetics and pharmacodynamics of MEDI0680, a fully human anti-PD-1 monoclonal antibody, in patients with advanced malignancies.

MEDI0680 is a humanized immunoglobulin monoclonal antibody that targets human programmed cell death protein 1 (PD-1) for the treatment of cancer. A population two-compartmental pharmacokinetic (PK) model and a sequential direct maximal effective drug concentration receptor occupancy (RO) model with baseline parameters were developed to quantify PK variability, identify significant covariates, and characterize the relationship between the PK and the RO of MEDI0680. A total of 58 patients with advanced malignancies received MEDI0680 by intravenous infusion at a dose of 0.1-20 mg/kg in a phase 1 study. The clearance was 0.27 L per day and the central volume of distribution (V 1 ) was 3.14 L, with a modest between-subject variability of 30 and 19%, respectively. None of the evaluated covariates showed any impact on PK parameters except for a nonclinically meaningful relevant impact of body weight on V 1 . The estimated half-maximal effective concentration for MEDI0680 binding to the PD-1 antigen was approximately 1.88 µg/mL. Visual predictive check results demonstrated good predictability of the final population PK-RO model. PK-RO simulations demonstrated that > 90% RO could be maintained in all subjects after a 20-mg/kg dose every 2 weeks (Q2W). Therefore, 20 mg/kg Q2W and an equivalently fixed dose of 1500 mg was recommended for phase 2 studies.