Semimechanistically Based Modeling of Pembrolizumab Time Varying Clearance Using Four Longitudinal Covariates in Patients with Non-Small Cell Lung Cancer.

Time varying clearance has been recently recognized in FDA drug labels for oncology monoclonal antibodies (mAbs). Pembrolizumab population CL at steady-state decreased about 20% from the first dose, and individual CL changes varied from 75% decrease to 25% increase, which were correlating with disease conditions. From mechanism of action perspective, this research explored the longitudinal covariate effect on pembrolizumab CL based on data from a Phase II/III clinical trial in patients with non-small cell lung cancer (NSCLC). Time courses of tumor size (SLD), lymphocyte count (LC), albumin (ALB) and lactate dehydrogenase (LDH) were first characterized separately and the post-hoc parameters of each individual patient were fixed in the subsequent semi-mechanistically-based modeling (Msmb ) analysis. Pembrolizumab time varying clearance was assumed to be associated with the patient's SLD, LC, ALB and LDH, and tumor related pembrolizumab CL (CLtumor ) was assumed to be a fraction (FCL) of total pembrolizumab clearance in the Msmb .