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 