Wilhelmus E.A. de Witte, Meindert Danhof, Elizabeth C.M de Lange, Piet H. van der Graaf
Leiden University, Division of pharmacology, LACDR, Leiden, the Netherlands.
Objectives: To predict in vivo target occupancy profiles and obtain a meaningful incorporation of drug-target binding kinetics in drug discovery, drug target binding kinetics should be integrated with other determinants of target occupancy and effect profiles, including pharmacokinetics, diffusion-limited binding and signal transduction. The aim of this study was to validate and explore previously published models which integrate pharmacokinetics, drug-target binding and diffusion-limited binding.
Methods: Initial simulations were performed in Berkeley Madonna to investigate the potential effect of diffusion-limited binding on target occupancy profiles under various conditions. Subsequently, a NONMEM code was written to describe pharmacokinetics, drug-target binding kinetics and diffusion-limited binding based on literature models[1,2]. Subsequently, the model performance was evaluated by comparing model predictions and published postiron emission tomography (PET) data for 18-F fallypride (a selective, high affinity dopamine D2 tracer) brain concentrations in plasma, cerebellum and striatum of rhesus monkeys[3]. These literature data were used to fit the NONMEM model both with and without diffusion-limited binding.
Results: The initial simulations demonstrated that diffusion-limited binding can increase the average target occupancy for drugs with fast drug-target dissociation kinetics. This effect of diffusion-limited binding decreases if the dissociation constant (Kd) increases and if an endogenous ligand is present. The developed NONMEM model enabled the description of in vivo brain concentrations of three subsequent injections of radiolabeled and unlabeled fallypride. The obtained model fits demonstrated the capability of both models (with and without diffusion-limited binding) to describe the data. Both models performed similarly in the description of striatum concentrations, but the overall model performance improved without diffusion-limited binding.
Conclusions: Diffusion-limited binding can increase the average target occupancy in a condition-dependent manner. Previously published models which integrate pharmacokinetics, drug-target binding and diffusion-limited binding were unable to demonstrate a significant influence of diffusion-limited binding on the in vivo receptor occupancy profile of fallypride.
This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking, K4DD grant n° 115366.
References:
[1] Coombs D, Goldstein B. Effects of the geometry of the immunological synapse on the delivery of effector molecules. Biophys. J.87:2215–20.
[2] Vauquelin G. Rebinding?: or why drugs may act longer in vivo than expected from their in vitro target residence time. Expert Opin. Drug Discov. 2010;5:927–41.
[3] Christian BT, Narayanan T, Shi B, Morris ED, Mantil J, Mukherjee J. Measuring the in vivo binding parameters of [18F]-fallypride in monkeys using a PET multiple-injection protocol. J. Cereb. blood flow Metab. 2004 24:309–22.
Reference: PAGE 24 () Abstr 3577 [www.page-meeting.org/?abstract=3577]
Poster: Drug/Disease modeling - Other topics