Whole-body PBPK with tissue TMDD modelling to predict determining parameters of target occupancy in tissues
Wilbert de Witte (1), Stephan Schaller (1)
(1) esqLABS GmbH, Saterland, Germany,
Objectives:
Target occupancy can be determined by many different parameters related to target binding, target internalization, and pharmacokinetics. The potential impact of these parameters is widely acknowledged, but a common understanding of the most influential parameters for different pharmaceutically relevant scenarios is not available.[1] This limited understanding is further complicated if (competitive) binding to multiple targets in multiple tissues is considered. Here we aim to improve this understanding.
Methods:
In this study, we have used both the small and large molecule PBPK models [2,3] in PK-Sim® and included target binding to two different targets and in different organs to study the impact of target binding kinetics, target concentration, localization, and internalization. We first focused on a general understanding of the determining parameters for a single target in a single tissue without endogenous competition. We have illustrated this understanding consequently in scenarios with multiple targets, multiple tissues, and endogenous competition. The target was located in the interstitial or in the intracellular space.
Results:
Our simulations demonstrated that for small molecules binding to interstitial targets, the equilibration between plasma and interstitial fluid is so fast that no tissue retention is caused by high target concentrations, and tissue selectivity based on target-mediated tissue retention is therefore not predicted. Target-mediated plasma retention is likely to be seen at relevant target concentrations and binding parameters, but only if the target concentration/affinity ratio is high enough. While this ratio for a target expressed in plasma or in slowly equilibrated tissue spaces only needs to exceed 1, this ratio needs to be higher for small molecule/interstitial target combinations in organs and depends on the target amount. For intracellularly expressed targets, on the other hand, a ratio larger than 1 was sufficient to induce target-mediated tissue retention. While target-mediated plasma or tissue retention can decrease the impact of kinetic selectivity, the presence of an endogenous competitor can increase this impact by only displacing the drug from the target with the fast dissociation rate constant. For large molecules, the generally low plasma clearance prevents the occurrence of target-mediated tissue retention at relevant target concentrations. Due to the slower equilibration between plasma and interstitial space, in scenarios with fast target-mediated internalization, depletion of free drug concentration for the tissue interstitial space is likely, which leads to limited target occupancy. A target internalization rate constant of 1 – 0.1/h can already be fast enough to generate such an effect.
Conclusions:
Previously identified concepts relating to the impact of drug-target binding kinetics and its dependence on other pharmacokinetic and target-related parameters were confirmed in a physiologically relevant context. This study showed the relevance of the target localization and amount for target-mediated retention for small molecules and of target internalization for large molecules. In general, using the physiological knowledge in computational models that predict the relevance of drug-target binding kinetics helps to refine the predictions to realistic scenarios.
References:
[1] Pressly MA, Peletier LA, Zheng S, et al. The quest for balance between capturing data and model complexity: a quantitative clinical pharmacology approach applied to monoclonal antibodies. CPT: Pharmacometrics & Systems Pharmacology. n/a(n/a). doi:10.1002/psp4.12927
[2] Willmann S, Lippert J, Sevestre M, Solodenko J, Fois F, Schmitt W. PK-Sim®: a physiologically based pharmacokinetic ‘whole-body’ model. BIOSILICO. 2003;1(4):121-124. doi:10.1016/S1478-5382(03)02342-4
[3] Niederalt C, Kuepfer L, Solodenko J, et al. A generic whole body physiologically based pharmacokinetic model for therapeutic proteins in PK-Sim. J Pharmacokinet Pharmacodyn. 2018;45(2):235-257. doi:10.1007/s10928-017-9559-4
