ArticleBritish journal of pharmacology2016
Effects of target binding kinetics on in vivo drug efficacy: koff , kon and rebinding.
Article in British journal of pharmacology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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Who cites it
56 citing papers in PubMed.
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- Homomultimeric FAP Inhibitor-Based Radioligands for Cancer Theranostics: Design Principles, Structure-Function Relationships, and Preclinical Performance.Molecules (Basel, Switzerland) · 2026Review
- Rebinding drives cellular retention of small-molecule drugs with abundant targets.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Adamantane-based inhibitors of the influenza A M2 proton channel: structure-based design, biological evaluation, and synthetic approaches.RSC medicinal chemistry · 2026Review
- A brain-penetrant P2X7R antagonist mitigates Alzheimer's disease pathology.bioRxiv : the preprint server for biology · 2026Article
- Protein structural dynamics in covalent drug design: insights from irreversible and reversible covalent inhibitors.RSC chemical biology · 2026Review
- Stability-Driven Pose Prediction and Ligand Design via Contact Persistence Analysis from Molecular Dynamics Simulations.Computational and structural biotechnology journal · 2026Article
- Interrogation of Small Molecules to Surface-Bound Aptamer Binding Kinetics with Electrochemical Aptamer-Based Sensors Using Intermittent Pulse Amperometry.Analytical chemistry · 2025Article
- In-Solution Characterization of Biomolecular Interaction Kinetics under Native Conditions.Analytical chemistry · 2025Article
- The Quasi-Bound State as a Predictor of Relative Binding Free Energy.Journal of chemical information and modeling · 2025Article
- Image-Guided Monitoring of Mitochondria and Blood-Brain Barrier Dysfunction in Amyotrophic Lateral Sclerosis Mice.Biomaterials research · 2025Article
- A universal cannabinoid CB1 and CB2 receptor TR-FRET kinetic ligand-binding assay.Frontiers in pharmacology · 2025Article
- Unraveling the Bivalent and Rapid Interactions Between a Multivalent RNA Recognition Motif and RNA: A Kinetic Approach.Biochemistry · 2024Article
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- Kinetic profiling of novel spirobenzo-oxazinepiperidinone derivatives as equilibrative nucleoside transporter 1 inhibitors.Purinergic signalling · 2024Article
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- An integrated modelling approach for targeted degradation: insights on optimization, data requirements and PKPD predictions from semi- or fully-mechanistic models and exact steady state solutions.Journal of pharmacokinetics and pharmacodynamics · 2023Article
- Unraveling the Mechanism of Epichaperome Modulation by Zelavespib: Biochemical Insights on Target Occupancy and Extended Residence Time at the Site of Action.Biomedicines · 2023Article
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Abstract
background and purposeOptimal drug therapy often requires continuing high levels of target occupancy. Besides the traditional pharmacokinetic contribution, target binding kinetics is increasingly considered to play an important role as well. While most attention has been focused on the dissociation rate of the complex, recent reports expressed doubt about the unreserved translatability of this pharmacodynamic property into clinical efficacy. 'Micro'-pharmacokinetic mechanisms like drug rebinding and partitioning into the cell membrane may constitute a potential fix. EXPERIMENTAL APPROACH: Simulations were based on solving differential equations. KEY
resultsBased on a selected range of association and dissociation rate constants, kon and koff , and rebinding potencies of the drugs as variables, their effects on the temporal in vivo occupancy profile of their targets, after one or multiple repetitive dosings, have here been simulated. CONCLUSIONS AND IMPLICATIONS: Most strikingly, the simulations show that, when rebinding is also taken into account, increasing kon may produce closely the same outcome as decreasing koff when dosing is performed in accordance with the therapeutically most relevant constant [Lmax ]/KD ratio paradigm. Also, under certain conditions, rebinding may produce closely the same outcome as invoking slow diffusion of the drug between the plasma compartment and a target-containing 'effect' compartment. Although the present simulations should only be regarded as a 'proof of principle', these findings may help pharmacologists and medicinal chemists to devise ex vivo and in vitro binding kinetic assays that are more relevant and translatable to in vivo settings.
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