Drug-induced liver injury (DILI) is of primary concern in drug development. Nearly half of all drugs entering clinical trials will fail because of some form of serious toxicity that was missed in preclinical studies, costing the industry billions of dollars.1,2 Although the liver can regenerate itself, liver injury can permanently impair its self-regenerative capacity, thus underscoring the need for non-hepatotoxic therapeutics.
The liver is the primary site of xenobiotic control, as drugs are metabolized by cellular enzymes present in hepatocytes. Drugs may be detoxified or made toxic by metabolism. Liver damage may be caused or exacerbated by drug-drug interactions and drug-transporter interactions, where hepatic uptake or excretion of the drug or its metabolite is inhibited.
Currently, conventional cell-based in vitro culture systems used to predict drug-induced liver injury include sandwich and monolayer cultures as well as suspensions of primary hepatocytes. Primary hepatoctyes dedifferentiate and display a precipitous decline in phenotypic function within days in these conventional culture methods, precluding their use in long-term toxicity studies and severely limiting their ability to predict clinical outcomes.
HepatoPac from Hepregen Corporation (Medford, Mass.) is a bio-engineered hepatocyte coculture platform in which primary hepatocytes are organized in domains of empirically optimized dimensions and surrounded by supportive non-parenchymal cells. HepatoPac technology exploits the ability of primary hepatocytes to respond to chemical stimuli (i.e., exposure to xenobiotics), while extending the phenotypic and functional stability of these cells in culture.
These cocultures result in a high-fidelity, in vitro tissue model that is proven to provide a range of liver-specific functions for greater than 4 weeks. Enzyme activity, cell polarization, albumin and urea synthesis and expression of transporter proteins are maintained throughout the culture period.3
The platform’s longevity in culture permits scientists to dose this coculture system at physiologically relevant drug concentrations over longer periods of time than was previously possible. This feature allows HepatoPac to more closely mimic the in vivo condition, thus enabling detection and prediction of hepatoxicity due to chronic dosing. In addition, the platform’s multi-well format can be used with existing industry automation for high-throughput screening.
The ability to mimic in vivo liver physiology lends the system to a broad range of applications including preclinical toxicity screening, metabolite identification, drug stability, drug-drug interactions, drug-transporter interactions, enzyme induction and clearance studies. HepatoPac can be used to identify and detect low, medium and high-turnover compounds. Furthermore, studies show that transporter uptake and efflux activities are higher and more stable in HepatoPac than observed in the current gold standard in vitro culture systems. This technology can be implemented early in the drug development process, decreasing the incidence of adverse clinical outcomes resulting from toxic pharmaceuticals.
1. Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov. 2004;3(8):711-5.
2. Neumann EK. Combining drug toxicity knowledge. Bio-IT World. July/August 2006. http://www.bio-itworld.com/. Accessed October 3, 2013.
3. Khetani SR, Bhatia SN. Microscale culture of human liver cells for drug development. Nat Biotechnol. 2008;26(1):120-6.