Time‐dependent clearance can confound exposure–response analysis of therapeutic antibodies: A comprehensive review of the current literature

Abstract

AbstractExposure–response (ER) analysis is used to optimize dose and dose regimens during clinical development. Characterization of relationships between drug exposure and efficacy or safety outcomes can be utilized to make dose adjustments that improve patient response. Therapeutic antibodies typically show predictable pharmacokinetics (PK) but can exhibit clearance that decreases over time due to treatment. Moreover, time‐dependent changes in clearance are frequently associated with drug response, with larger decreases in clearance and increased exposure seen in patients who respond to treatment. This often confounds traditional ER analysis, as drug response influences exposure rather than the reverse. In this review, we survey published population PK analyses for reported time‐dependent drug clearance effects across 158 therapeutic antibodies approved or in regulatory review. We describe the mechanisms by which time‐dependent clearance can arise, and evaluate trends in frequency, magnitude, and time scale of changes in clearance with respect to indication, mechanistic interpretation of time‐dependence, and PK modeling techniques employed. We discuss the modeling and simulation strategies commonly used to characterize time‐dependent clearance, and examples where time‐dependent clearance has impeded ER analysis. A case study using population model simulation was explored to interrogate the impact of time‐dependent clearance on ER analysis and how it can lead to spurious conclusions. Overall, time‐dependent clearance arises frequently among therapeutic antibodies and has spurred erroneous conclusions in ER analysis. Appropriate PK modeling techniques aid in identifying and characterizing temporal shifts in exposure that may impede accurate ER assessment and successful dose optimization.