Understanding interspecies differences in Drug-Induced Liver Injury (DILI) events is critical for translational risk assessment and reducing compound attrition during drug development. Although non-clinical safety testing in two animal species persists, the ability to predict human responses alongside animal is critical to progress drug candidates to the clinic, or to pause and better understand adverse outcomes if required. Organ-on-chip (OOC) systems are essential to bridge the translational gap between animal models and human outcomes, improving predictivity of non-clinical safety assessments. To address this, we employed the PhysioMimix® OOC System to develop a DILI assay optimized for primary hepatocytes derived from human, rat, and canine. 3D liver microtissues were formed and cultured in the liver microphysiological system (MPS) under dynamic perfusion. Each liver microtissue demonstrated stable species-specific functionality (CYP, albumin, urea) for up to 14 days.To evaluate differential hepatotoxic responses across species, we applied a panel of reference compounds known to elicit DILI alongside structural analogues with no known human DILI liability. A daily dosing regimen was applied at a 7-dose concentration range for 4 days. Functional biomarkers (urea, albumin) were assessed in parallel with clinical liver injury markers (LDH, ALT), offering comprehensive readout of hepatocellular health and toxicity. The system successfully captured known species-specific toxicities. For example, nefazodone (DILI Rank 8) induced hepatotoxicity in human and rat with greater sensitivity compared to canine. In human and rat, urea and albumin showed decreases at similar IC50 values. Buspirone (DILI Rank 3) was demonstrated as safe across all species. In canine hepatocytes, neither urea nor LDH indicated toxicity with nefazodone or buspirone treatment. Albumin emerged as a sensitive marker across all three species, with nefazodone inducing dose-dependent decrease at a lower IC50 than other markers. This study demonstrates the value of integrating animal and human liver MPS models for DILI assessment to improve cross-species interpretation. This approach offers a path toward improved human risk prediction by identifying species-specific liabilities earlier in the development pipeline. As regulatory interest in MPS continues to grow, these platforms have potential to better inform, complement, or reduce reliance on traditional models for liver safety risk assessments.
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