Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, China (X.L.); Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (X.L., Y.C.); and Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical, Sciences, State University of New York at Buffalo, Buffalo, New York (W.J.J.).
Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, China (X.L.); Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (X.L., Y.C.); and Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical, Sciences, State University of New York at Buffalo, Buffalo, New York (W.J.J.)
J Pharmacol Exp Ther. 2018 Oct;367(1):1-8. doi: 10.1124/jpet.118.250134. Epub 2018 Jul 12.
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 ) 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 ) are generally favored, but a plateau effect is present for antibodies with low dissociation rates (). Etanercept is often regarded as a fast tumor necrosis factor- (TNF-) binder (high ) despite comparable binding affinity (, /) 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- 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.
对于针对可溶性配体的治疗性生物制剂，靶标抑制的幅度和持续时间会影响其治疗效果。许多因素都与靶标抑制有关，但尚未考虑靶组织间质液周转率。受依那西普在类风湿关节炎中疗效很高而在克罗恩病中疗效有限这一事实的启发，我们开发了一个最小的基于生理学的药代动力学模型，以研究组织液周转率对可溶性靶标抑制的作用，并评估结合常数和组织液周转率之间的相互关系。靶组织中的间质液周转率被发现强烈影响靶标结合动力学。对于间质液周转率低的组织，稳定结合剂（低 ）表现出更大的靶标抑制作用，但疗效通常受到药物-靶复合物的积累限制。对于间质液周转率高的组织，快速结合剂（高 ）通常更有利，但对于解离率低的抗体（）存在平台效应。尽管依那西普与阿达木单抗和英夫利昔单抗的结合亲和力相当（， /），但依那西普通常被认为是一种快速肿瘤坏死因子-（TNF-）结合剂（高 ）。克罗恩病主要涉及结肠，其间质液周转率比关节炎相关关节滑膜慢；这可能解释了为什么依那西普在克罗恩病中对 TNF-的抑制作用不佳。这项研究强调了在评估与可溶性抗原结合的治疗性抗体时组织间质液周转率的重要性。
