In vitro to in vivo extrapolation and species response comparisons for drug-induced liver injury (DILI) using DILIsym™: a mechanistic, mathematical model of DILI

• Published in: Journal of pharmacokinetics and pharmacodynamics 2012-10, Vol.39 (5), p.527-541
• Main Authors: Howell, Brett A., Yang, Yuching, Kumar, Rukmini, Woodhead, Jeffrey L., Harrill, Alison H., Clewell, Harvey J., Andersen, Melvin E., Siler, Scott Q., Watkins, Paul B.
• Format: Article
• Language: English
• Subjects: Animals; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Chemical and Drug Induced Liver Injury - etiology; Chemical and Drug Induced Liver Injury - genetics; Chemical and Drug Induced Liver Injury - metabolism; Drug-Related Side Effects and Adverse Reactions; Humans; Mice; Mice, Inbred C57BL; Models, Theoretical; Original Paper; Pharmaceutical Preparations - metabolism; Pharmacology/Toxicology; Pharmacy; Rats; Rats, Sprague-Dawley; Species Specificity; Veterinary Medicine/Veterinary Science
• ISSN: 1567-567X; 1573-8744
• DOI: 10.1007/s10928-012-9266-0

Drug-induced liver injury (DILI) is not only a major concern for all patients requiring drug therapy, but also for the pharmaceutical industry. Many new in vitro assays and pre-clinical animal models are being developed to help screen compounds for the potential to cause DILI. This study demonstrates that mechanistic, mathematical modeling offers a method for interpreting and extrapolating results. The DILIsym™ model (version 1A), a mathematical representation of DILI, was combined with in vitro data for the model hepatotoxicant methapyrilene (MP) to carry out an in vitro to in vivo extrapolation. In addition, simulations comparing DILI responses across species illustrated how modeling can aid in selecting the most appropriate pre-clinical species for safety testing results relevant to humans. The parameter inputs used to predict DILI for MP were restricted to in vitro inputs solely related to ADME (absorption, distribution, metabolism, elimination) processes. MP toxicity was correctly predicted to occur in rats, but was not apparent in the simulations for humans and mice (consistent with literature). When the hepatotoxicity of MP and acetaminophen (APAP) was compared across rats, mice, and humans at an equivalent dose, the species most susceptible to APAP was not susceptible to MP, and vice versa. Furthermore, consideration of variability in simulated population samples (SimPops™) provided confidence in the predictions and allowed examination of the biological parameters most predictive of outcome. Differences in model sensitivity to the parameters were related to species differences, but the severity of DILI for each drug/species combination was also an important factor.