Advances in binding kinetics and mechanistic PK/PD modelling

Abstract

It has been a year since we held the ‘Binding Kinetics and Mechanistic PK/PD modelling’ meeting in Cambridge. The event was a roaring success with some of the best mechanistic enzymologists and PK/PD modellers attending and presenting their work at the event. Now, it gives me immense pleasure to present to you these three reviews summarising the advances discussed at the meeting, covering the highlights and nuances of how binding kinetics has played a major role in redefining the quantification of drug–target interactions and PK/PD modelling.

For small-molecule drug discovery, binding kinetics is critical in understanding how the matrix events of small-molecule association, small-molecule dissociation (and the attendant residence time), small-molecule half-life in systemic circulation (and, as an extension, at the site of action) and the half-life of the protein target coalesce together to give us the therapeutic index and window. The latter parameters are essential to appreciate efficacy in light of toxicity (the latter could be on-target and/or off-target dependent on the affinity and kinetics of the small molecule's interaction with the target of interest versus other proteins). As we transition from small molecules to large molecules and from predominantly reversible equilibrium inhibition to other modalities such as non-equilibrium irreversible and degradation, these tenets are becoming all the more relevant in quantifying efficacy weighed against potential toxicity. The correct assessment of the concentration of a small molecule at its site of action is very important. This would depend on (1) intravascular versus extravascular administration with potential first pass depletion, (2) deciding on the strategy of administration as a single bolus dose versus infusion, (3) measuring the outcomes of diuretic effects in clearing the small molecule from systemic circulation as a function of dose concentration, (4) dose frequency and dosing mode and (5) assessing the effects of type I and type II mechanisms in metabolizing the small molecule with potential excretion; and are factors that have been traditionally considered very critical in understanding the concentration and, thus, efficacy of the action of small molecules and have been historically classed as aspects of pharmacokinetic modelling. Likewise, the equilibrium measure of affinity, signifying the potency of the small molecule's interaction with its target of interest, has been quantified by pharmacodynamic measures. These measures, in spite of their limitation in understanding the time evolution of the small molecule's interaction with their target of interest, have supported decision making for small-molecule drug discovery cascades.

However, with emergent modalities such as PROTAC (where a bivalent ligand recruits the protein of interest to an E3 ligase resulting in its ubiquitination and subsequent degradation), molecular glues (where a small molecule facilitates protein–protein interaction between traditionally non-interacting or weakly interacting proteins by changing the molecular surface: the latter could be to a cognate E3 ligase facilitating ubiquitination and subsequent degradation) and irreversible inhibition (where electrophilic groups of the small molecule can form either a reversible or irreversible adduct with a nucleophilic residue on the protein target of interest), traditional metrics of PK/PD modelling fall short in their predictability potential. This can be appropriately rectified by relying on aspects of mechanistic PK/PD modelling, a term emphasizing the incorporation of time evolution of small-molecule target interactionand the half-life of the protein into traditional PK/PD modelling approaches.

In the ever-evolving landscape of drug discovery and development, the translation of in vitro potency (closed thermodynamic system) to in vivo efficacy and safety (open thermodynamic system) remains a formidable challenge. Traditional pharmacological metrics, while informative, often fall short in capturing the dynamic nature of drug–target interactions in vivo. The emerging focus on residence time, target half-life quantitation and ligand-receptor kinetics presents a promising avenue for addressing these limitations. The shift towards a more nuanced understanding of drug–target interactions has already begun to yield promising results, with the integration of residence time and ligand–receptor kinetics into early-stage drug discovery leading to the identification of clinical candidates with improved in vivo efficacy and safety profiles. As we delve deeper into the intricacies of drug–target interactions, the potential for transformative changes in the drug discovery process becomes increasingly evident. These reviews make significant contributions that highlight the importance of these emerging concepts in the field of binding kinetics and mechanistic PK/PD modelling in aiding drug discovery decisions with the potential of stemming attrition (Hill & Kilpatrick, 2024; Knockenhauer & Copeland, 2024; Liu et al., 2024) and hopefully will serve as definitive references for anyone interested in these topics.

The author is an employee of AstraZeneca PLC and declares no conflict of interest.