Mechanistic models enable the rational use of <i>in vitro</i> drug-target binding kinetics for better drug effects in patients

Witte, Wilhelmus E. A. de; Wong, Yin Cheong; Nederpelt, Indira; Heitman, Laura H.; Danhof, Meindert; Graaf, Piet H. van der; Gilissen, RMCA mammalogy - Emmanuel; Lange, Elizabeth C. M. de

doi:10.1517/17460441.2016.1100163

Cited by 28 publications

(28 citation statements)

References 103 publications

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“…Future advances will involve the routine implementation of methods to measure binding kinetics in the cell, such as those derived from NanoBRET, 76 approaches to quantify in vivo target engagement by reversible inhibitors, 77 and the further development and parametrization of advanced mathematical models that better simulate and predict drug–target interactions in the complex environment of the human body. 21,22,24,26 …”

Section: Summary and Future Directionsmentioning

confidence: 99%

Drug–Target Kinetics in Drug Discovery

Tonge

2017

ACS Chem. Neurosci.

215

235

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The development of therapies for the treatment of neurological cancer faces a number of major challenges including the synthesis of small molecule agents that can penetrate the blood brain barrier (BBB). Given the likelihood that in many cases drug exposure will be lower in the CNS than in systemic circulation, it follows that strategies should be employed that can sustain target engagement at low drug concentration. Time dependent target occupancy is a function of both the drug and target concentration as well as the thermodynamic and kinetic parameters that describe the binding reaction coordinate, and sustained target occupancy can be achieved through structural modifications that increase target (re)binding and/or that decrease the rate of drug dissociation. The discovery and deployment of compounds with optimized kinetic effects requires information on the structure-kinetic relationships that modulate the kinetics of binding, and the molecular factors that control the translation of drug-target kinetics to time-dependent drug activity in the disease state. This review first introduces the potential benefits of drug-target kinetics, such as the ability to delineate both thermodynamic and kinetic selectivity, and then describes factors, such as target vulnerability, that impact the utility of kinetic selectivity. The review concludes with a description of a mechanistic PK/PD model that integrates drug-target kinetics into predictions of drug activity.

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Section: Summary and Future Directionsmentioning

confidence: 99%

Drug–Target Kinetics in Drug Discovery

Tonge

2017

ACS Chem. Neurosci.

215

235

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“…For understanding the influence of target binding kinetics on in vivo drug action, it is therefore important to have adequate information on the unbound concentration of the compound in plasma and in brain regions where the target resides. Both ex vivo and in vivo TO of drugs can be evaluated in experimental animals using both invasive and noninvasive methods [47] The ex vivo approach uses tissue slice autoradiography, or biochemical measures of TO, wherein the fraction of total target binding sites occupied by the drug is inferred from the residual binding capacity of a radiotracer added to the postmortem tissue ex vivo. The in vivo approach, on the other hand, measures the displacement of the radiotracer from the target tissue when both the drug and the radiotracer are administered to the living animal.…”

Section: Target Binding Kineticsmentioning

confidence: 99%

“…The measurement of TO and target site PK can provide valuable insight into the driving factors for the time course of drug action. However, additional factors such as target turnover/desensitization, endogenous ligand binding, and signal transduction can also influence the time course of drug action and need to be taken into account [47].…”

Section: Target Binding Kineticsmentioning

confidence: 99%

Novel CNS drug discovery and development approach: model-based integration to predict neuro-pharmacokinetics and pharmacodynamics

Lange

Brink

Yamamoto

et al. 2017

Expert Opinion on Drug Discovery

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Introduction: CNS drug development has been hampered by inadequate consideration of CNS pharmacokinetic (PK), pharmacodynamics (PD) and disease complexity (reductionist approach). Improvement is required via integrative model-based approaches. Areas covered: The authors summarize factors that have played a role in the high attrition rate of CNS compounds. Recent advances in CNS research and drug discovery are presented, especially with regard to assessment of relevant neuro-PK parameters. Suggestions for further improvements are also discussed. Expert opinion: Understanding time-and condition dependent interrelationships between neuro-PK and neuro-PD processes is key to predictions in different conditions. As a first screen, it is suggested to use in silico/in vitro derived molecular properties of candidate compounds and predict concentrationtime profiles of compounds in multiple compartments of the human CNS, using time-course based physiology-based (PB) PK models. Then, for selected compounds, one can include in vitro drug-target binding kinetics to predict target occupancy (TO)-time profiles in humans. This will improve neuro-PD prediction. Furthermore, a pharmaco-omics approach is suggested, providing multilevel and paralleled data on systems processes from individuals in a systems-wide manner. Thus, clinical trials will be better informed, using fewer animals, while also, needing fewer individuals and samples per individual for proof of concept in humans. ARTICLE HISTORY

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“…Drug–target binding kinetics is mostly measured in vitro to select the “best” drug candidates. However, to predict a clinical drug effect from in vitro experiments, all determinants influencing the drug's fate in the path from drug intake to drug effect in vivo need to be taken into account . These determinants include not only drug concentrations at the target site and target binding kinetics, but also other factors such as competition with the natural ligands that normally bind to the target and the biological effect of binding (Fig.…”

Section: K4dd (Kinetics For Drug Discovery)mentioning

confidence: 99%

Public–Private Partnerships in Lead Discovery: Overview and Case Studies

Gottwald

Becker

Bahr

et al. 2016

Archiv der Pharmazie

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The pharmaceutical industry is faced with significant challenges in its efforts to discover new drugs that address unmet medical needs. Safety concerns and lack of efficacy are the two main technical reasons for attrition. Improved early research tools including predictive in silico, in vitro, and in vivo models, as well as a deeper understanding of the disease biology, therefore have the potential to improve success rates. The combination of internal activities with external collaborations in line with the interests and needs of all partners is a successful approach to foster innovation and to meet the challenges. Collaboration can take place in different ways, depending on the requirements of the participants. In this review, the value of public-private partnership approaches will be discussed, using examples from the Innovative Medicines Initiative (IMI). These examples describe consortia approaches to develop tools and processes for improving target identification and validation, as well as lead identification and optimization. The project "Kinetics for Drug Discovery" (K4DD), focusing on the adoption of drug-target binding kinetics analysis in the drug discovery decision-making process, is described in more detail.

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Mechanistic models enable the rational use of in vitro drug-target binding kinetics for better drug effects in patients

Cited by 28 publications

References 103 publications

Drug–Target Kinetics in Drug Discovery

Drug–Target Kinetics in Drug Discovery

Novel CNS drug discovery and development approach: model-based integration to predict neuro-pharmacokinetics and pharmacodynamics

Public–Private Partnerships in Lead Discovery: Overview and Case Studies

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