Evaluation of a microfluidic based cell culture platform with primary human hepatocytes for the prediction of hepatic clearance in human

Abstract

Integral to the discovery of new pharmaceutical entities is the ability to predict in vivo pharmacokinetic parameters from early stage in vitro data generated prior to the onset of clinical testing. Within the pharmaceutical industry, a whole host of assay methods and mathematical models exist to predict the in vivo pharmacokinetic parameters of drug candidates. One of the most important pharmacokinetic properties of new drug candidates predicted from these methods and models is the hepatic clearance. Current methods, while useful, are still limited in their predictive efficacy. In order to address this issue, we have established a novel microfluidic in vitro culture system, the patented HμREL® device. The device comprises multiple compartments that are designed to be proportional to the physiological architectures and enhanced with the consideration of flow. Here we demonstrate the functionality of the liver-relevant chamber in the HμREL® device, and the feasibility of utilizing our system for predicting hepatic clearance. Cryopreserved human hepatocytes from a single donor were seeded within the HμREL® device to predict the in vivo hepatic clearance (CLH) of six marketed model compounds (carbamazepine, caffeine, timolol, sildenafil, imipramine, and buspirone). The intrinsic clearance rates from static culture controls, as well as clearance rates from the HμREL® device were subsequently compared to in vivo data available from the literature.

Modeling Therapeutic Antibody–Small Molecule Drug-Drug Interactions Using a Three-Dimensional Perfusable Human Liver Coculture Platform

“…These methods have shown promise in the evaluation of hepatic drug metabolism, DILI, and PK (Chao et al, 2009;Kostadinova et al, 2013;Messner et al, 2013;Ballard et al, 2016). The LiverChip platform offers continuous perfusion of oxygenated medium through a scaffold containing microchannels for 3D cell culture under flow.…”

“…Recently, there have been several platforms introduced that offer the potential for long-term, multiweek primary human hepatocyte culture, which would provide researchers the ability to model more complex interactions involving chronic dosing effects, low-clearance compound and drug accumulation, human-specific metabolite identification, DILI, and the effects of chronic inflammation (Chao et al, 2009;Kostadinova et al, 2013;Messner et al, 2013;Ballard et al, 2016). There are several approaches that can increase in vitro hepatic performance and concomitant physiologic relevance, including three-dimensional (3D) cell culture, application of media flow and shear conditions to mimic natural tissue, and cocultures with liver nonparenchymal cell types such as Kupffer cells (KCs), liver sinusoidal endothelial cells, and hepatic stellate cells (LeCluyse et al, 2012;Ebrahimkhani et al, 2014).…”

Cytochrome P450-Dependent Metabolism in HepaRG Cells Cultured in a Dynamic Three-Dimensional Bioreactor

“…It is known that nonspecific binding of substances to material in different types of bioreactor systems (including conventional 2D systems) can be a problem (Toepke and Beebe, 2006;Chao et al, 2009). The nonspecific binding properties of the substances used in the present study were not investigated.…”

Stem Cells for HUMAN Hepatic Tissue Engineering

“…Furthermore, in a static well the system is usually mass transport limited; flow can remedy this by the addition of convective mode of mass transport. A variety of devices have been developed for this purpose [68][69][70], and in particular to determine parameters for multi-compartmental physiologically-based pharmacokinetic (PBPK) models, Figure 6. For example, a multi-tissue compartmental device has been developed that incorporates a large liver compartment for the assessment of drug absorption both in the liver as well as in other metabolizing tissue types [71][72][73].…”