Cultural Communication—for Hepatocytes
Over 900 drugs have been reported to cause liver injury, and hepatotoxicity is second only to cardiotoxicity as a cause of drug withdrawal from clinical trials or the market. Use of in vitro human liver cell cultures may be helpful in detecting drugs associated with hepatic adverse drug reactions in preclinical development.
Unfortunately, current model systems such as human primary hepatocyte monocultures and sandwich cultures lose functionality within a few days. Improved, long-lasting hepatocyte cultures could revolutionize toxicity testing. Okey Ukairo, Ph.D., senior principal scientist, ADME/Tox services, at Hepregen, discussed his company’s work with a novel hepatocyte co-culture system for drug-toxicity testing.
“Published reports show a higher incidence of drug attrition due to hepatotoxicity in early and late clinical drug development. What this tells me, and many people agree, is that the current models for liver toxicity testing during preclinical development are inadequate,” he said.
Conventional in vitro liver model systems (e.g., sandwich cultures of human hepatocytes) are limited in their ability to maintain hepatocyte functionality over an extended period of time. Even animal models such as rat, monkey, and dog often do not accurately translate to what is observed in humans.
Hepregen has developed a micropatterned hepatocyte co-culture platform (HepatoPac) for studying drug metabolism and toxicities.
“Human hepatocytes in the HepatoPac platform retain their in vivo-like morphology and retain sustained hepatic functions for three to four weeks in vitro,” explained Dr. Ukairo. Utilizing HepatoPac, toxicity screening, mechanistic toxicology, and identification of drug metabolites can all be performed in vitro with increased confidence of the clinically relevant predictive value, he added.
In one particular collaboration with pharmaceutical scientists, Hepregen compared its human hepatocyte co-culture platform with a sandwich system using commercially available compounds such as clozapine, isoniazid, nifidipine, and acetazolamide, whose toxicity profiles are well-characterized.
“In that study, Hepregen was able to accurately predict over 70 percent of the drugs that cause liver toxicity,” explained Dr. Ukairo. Beyond safety screening, the platform has the potential to be applied broadly in the drug discovery process for target validation, disease model creation and biomarker discovery, continued Dr. Ukairo, who pointed out that there is also potential to utilize stem-cell-derived hepatocytes in the system.