Role of Interstitial Fluid Turnover on Target Suppression by Therapeutic Biologics Using a Minimal Physiologically Based Pharmacokinetic Model.

Abstract

For therapeutic biologics against soluble ligands, the magnitude and duration of target suppression affect their therapeutic efficacy. Many factors have been evaluated in relation to target suppression but the interstitial fluid turnover rate in target tissues has not been considered. Inspired by the fact that etanercept exerts limited efficacy in Crohn's disease despite its high efficacy in rheumatoid arthritis, we developed a minimal physiologically based pharmacokinetic model to investigate the role of the tissue fluid turnover rate on soluble target suppression and assessed the interrelationships between binding constants and tissue fluid turnover. Interstitial fluid turnover rates in target tissues were found to strongly influence target binding kinetics. For tissues with low fluid turnover, stable binders (low koff) exhibit greater target suppression, but efficacy is often restricted by accumulation of the drug-target complex. For tissues with high fluid turnover, fast binders (high kon) are generally favored, but a plateau effect is present for antibodies with low dissociation rates (koff). Etanercept is often regarded as a fast tumor necrosis factor-α (TNF-α) binder (high kon) despite comparable binding affinity (KD, koff/kon) with adalimumab and infliximab. Crohn's disease largely involves the colon, a tissue with relatively slower fluid turnover than arthritis-associated joint synovium; this may explain why etanercept exerts poor TNF-α suppressive effect in Crohn's disease. This study highlights the importance of tissue interstitial fluid turnover in evaluation of therapeutic antibodies bound to soluble antigens.