Approximately 50-60% of drugs that proceed through pre-clinical testing ultimately fail in humans, primarily because human metabolism and toxicity are difficult to predict in animals or in vitro. HepatoPac®, an in vitro micropatterened co-culture of primary hepatocytes and supportive stromal cells, is a proven, highly predictive tool for pre-clinical and clinical toxicity studies. Predictive tools such as HepatoPac, when deployed early in drug development, may help reduce the number of late stage failures thereby saving money and time.
using our Human HepatoPac Tox Kit or through Hepregen Contract Toxicity Services. HepatoPac co-cultures are available for a variety of animal species including rat, monkey and dog enabling you to choose a pre-clinical animal model best suited to predict human toxicity.
One pharmaceutical company estimated that clinical failures based on liver toxicity alone have cost them more than $2 billion in the last decade. Drug Induced Liver Injury (DILI), a leading cause of pre-launch and post-market attrition, is often identified extremely late in drug development, when enormous amounts of time and money have been spent on a potential drug. Established in vitro models for detecting hepatotoxicity have extremely short-lived functionality (3-5 days) that does not allow for chronic dosing, making it difficult to distinguish between drug-induced toxicity and the natural decline of hepatocyte health. Compounds must often be dosed at higher than efficacious concentrations to see toxicity in the short window of functionality. This can lead to results that are not clinically relevant and to problems of compound solubility. Even with highly sensitive high content imaging readouts, current sensitivities of sandwich cultures are estimated to be approximately 50 to 60% . There is a need for an improved in vitro model of primary human liver tissue that is highly predictive of clinical outcomes to significantly reduce the number of late stage drug failures.
HepatoPac's ability to closely mimic the human liver's functionality as well as its extended in vitro viability make it well suited for use in predictive toxicology studies. Hepatocytes in HepatoPac co-cultures retain their in vivo-like morphology, express liver genes, metabolize compounds using active Phase I/II drug metabolism enzymes, secrete diverse liver-specific products, and display functional bile canaliculi for up to 4 weeks in vitro. The extended HepatoPac functionality allows for compound dosing at clinically relevant concentrations with repeat dosing over longer periods of time to detect chronic toxicity.
HepatoPac - Proven Predictive Power
Hepatocyte Imaging Assay Technology (HIAT; Xu et al., 2008), was reported to have a positive rate of 50-60% for predicting human toxicity with a low false-positive rate of 0-5%. Human HepatoPac was tested with a set of 45 compounds (35 DILI positive and 10 DILI negative compounds) to compare its predictive power versus the established HIAT and demonstrated improved sensitivity without a loss of specificity. Human HepatoPac co-cultures had 90% specificity with 69% sensitivity.
HepatoPac - Choosing the Right Animal Model
The gold standards for toxicological evaluation of substances are whole rodent models; however, species-specific variations between rodents and humans can be significant, especially in liver-specific metabolic pathways (i.e. CYP450), which severely limits the utility of animal models for predicting human-specific responses. HepatoPac co-cultures are available for a variety of species including human, monkey, rat and dog enabling researchers to identify the animal model that most closely predicts human toxicity for use in future pre-clinical studies.
Type Title Publication The Use of Micropatterned Co-Cultures to Detect Compounds that Cause Drug induced Liver Injury in Humans. Toxicol. Sci. 132 (1): p 107-117, (2013). Poster Evaluation of the Toxicity Profiles of Selected Bioactivated Compounds in Primary Rat Hepatocytes Cultured in Micropatterned Cocultures Poster Micropatterned Primary Hepatocyte Co-Cultures for Drug Metabolism and Toxicity Studies Application Note HepatoPac®: A Bioengineered Micro-liver Platform for Predictive and Mechanistic Toxicology Studies