SELF-ASSEMBLING HEPATOCYTE CO-CULTURE MODEL PROVIDES RELEVANT DRUG METABOLIZING ENZYME RESPONSES ACROSS HUMAN AND NONCLINICAL SPECIES

Abstract

In vivo nonclinical animal testing can reveal hepatic drug metabolizing enzyme (DME) induction profiles which are unwanted in the clinical setting. Due to the challenges of species differences in nuclear hormone receptor expression, it is important to understand whether findings in animals translate to effects in humans. Drug-drug interactions, induction, or inhibition of phase I or II DMEs, multi-organ toxicities and toxic metabolite formation can unfavorably impact a molecule’s development and safety profile. The classic in vitro method of sandwich cultured hepatocytes (SCH) in monoculture format routinely falls short of providing expected and consistent induction responses, especially those from nonclinical species. This work sought to assess the DME induction performance of different in vitro hepatic culture configurations using primary hepatocytes isolated from human, rat, dog and cynomolgus monkey. Cultures of primary hepatocytes consisted of self-assembling co-cultures (SACC), micropatterned co-culture hepatocytes (MPCC) and SCH. Each model system was evaluated using a test set of compounds with known species- and pathway-specificity for cytochrome P450 enzyme induction. Cultures were treated consecutively for two days and mRNA fold-induction relative to vehicle controls was assessed. Our results demonstrated SACC cultures provided better reliability and specificity of responses than MPCC and SCH systems across all species evaluated. These results suggest SACC cultures provide a better solution for screening potential DME induction profiles across species.