Workpackage 3: Link to the clinic: building the models to improve prediction of the kinetics of drug effect in humans

Understanding the interaction of drug molecules with their protein targets is important to predict how fast a drug effect will (dis)appear in a patient. Drug-target binding kinetics are mostly measured in vitro to select the "best" drug candidates (WP1 & WP2). However, to predict a clinical drug effect from in vitro experiments, understanding all determinants of the drug effect is necessary. These determinants include drug concentrations at the target site and target binding kinetics, but also other factors such as competition with body compounds that normally bind to this target (endogenous competition) and the impact of binding to the target to induce a signalling cascade (target activation). The exact role of these factors in the determination of drug effect is unfortunately poorly understood.

"To determine the influence of binding kinetics on drug effect, we need to take into account all events in the path from drug intake to drug effect."

Within the consortium leading academic and industry research groups are collaborating with the aim to improve the translation of preclinical in vitro findings to clinical drug treatment. To improve this translation, WP3 intends to build comprehensive pharmacokinetic-pharmacodynamic (PKPD) models using a combination of in vitro experiments, in vivo experiments and clinical data. These models take into account the time course of effect intensity in response to administration of a drug dose. It will enhance our understanding of the specific role of target binding kinetics in drug treatment and thereby enabling the prediction of drug treatment effect.

Figure 1. Overview of the different experiments and their output

It is important to understand that when a drug intervenes in body processes, the body can react to the drug action with the intent to restore body functioning as it was before. So, between drug intake and effect we need to take into account these so-called homeostatic feedback mechanisms (see fig 2).
To have the complete picture of drug effect we wish to answer two basic questions:
1) Which factors mediate the time course of drug effect after drug intake?
2) Which factors determine the feedback from the human body to drug action?

For the first question, we investigate pharmacokinetics, target binding kinetics [P. Tummino, 2008], target activation, endogenous competition [C. Endres, 1997],[G. Vauquelin, 2006] and the mechanisms of cellular signal transduction (figure 2). The second question is addressed by studying target regulation, cellular feedback and homeostatic feedback (figure 2).

Figure 2. Schematic representation of the position of binding kinetics in the generation of drug effect

A series of compounds that bind to the same target with different target binding kinetics is used to study the influence of target binding kinetics on drug effect. This series of compounds will be studied in a range of in vitro and in vivo studies to obtain maximal information on the influence of binding kinetics in all processes contributing to drug effect (figure 2).

Translation of our findings from in vitro experiments to in vivo preclinical and ultimately clinical studies will provide insight on the determinants of drug effect. To analyse and integrate the data on these factors, we use pharmacokinetic-pharmacodynamic (PKPD) modeling. This modeling will eventually enable the prediction of drug treatment effect in patients [A. Yassen, 2005].

WP3 at a glance:

  • 3 universities
  • 7 big pharmaceutical companies
  • 1 small/ medium sized enterprise

Expertise:

  • Pharmacology
  • Medicinal chemistry
  • Cellular modeling
  • Mechanistic PKPD-modeling.

Challenges:

  • In vivo binding kinetics estimation
  • Integration of cellular and system models
  • Response modeling

Workpackage leaders:

  • D. Huntjens PhD (Dymphy)
  • Prof. A. IJzerman PhD (Ad)

 

 

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