(BBSRC DTP) 3D microphysiological model of human kidney proximal tubule as in vitro tool to predict risk of renal drug-drug interactions and nephrotoxicity

Renal excretion and metabolism are important determinants of the local and systemic exposure of drugs and associated drug-drug interactions/ drug-induced nephrotoxicity. Current preclinical models and approaches in drug discovery poorly predict these events, as cellular models often lack the complexity to describe key mechanisms while animal models lack translational confidence to human. Recent years have seen an increase in availability and complexity of in vitro tools to investigate renal drug metabolism and transport. Advances in cell biology, combined with micro-engineering, resulted in a ‘next generation’ of in vitro kidney models that allow co-culture of multiple cell types, fluid flow (e.g., microfluidic devices such as ‘organ-on-a-chip’), and 3D cell culture system [1,2]. These systems show promising physiological features such as glucose reabsorption, active secretion and exhibit long-term viability (up to 28 days) [2]. However, the application of these technologies for mechanistic prediction of renal drug disposition and the translational value remains a challenge.

Physiologically-based pharmacokinetic (PBPK) modelling has been increasingly used in different stages of drug development; a particularly favourable feature of this computational modelling approach is its ability to extrapolate to untested scenarios (e.g., predict drug-drug interactions) and to patient population (e.g., renal impairment) by incorporating relevant information on physiology and specific drug properties in conjunction with mechanistic in vitro data [3]. The focus of PBPK modelling and this project is to predict and prevent in a prospective manner any drug related safety risk for the patient, not the treatment of the disease per se.

The objective of this project is to investigate different 2D and 3D cellular platforms (in conjunction with mechanistic modelling) as predictive tools for investigating risk of renal drug-drug interactions and nephrotoxicity. Drugs with reported clinically relevant transporter-mediated drug-drug interactions and/or nephrotoxicity (e.g., cidofovir) will be used for validation of the model predictions. Initial mechanistic in vitro kinetic studies will be performed in transfected cell lines expressing individual or multiple transporters to establish in vitro-in vivo extrapolation. Follow up in vitro studies will employ complex 3D microphysiological systems (kidney-on-the-chip) to investigate the interplay between multiple processes affecting renal drug disposition of selected drugs (also combination of drugs). Finally, mechanistic in vitro kinetic parameters will be integrated in the PBPK kidney models to assess translational ability of such data to predict drug-induced changes in renal exposure and any safety risk. The proposed inter-disciplinary and model-driven approach has strong foundations and builds upon previous and ongoing research in our group.