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

Abstract

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.

Prediction of Safety Margin and Optimization of Dosing Protocol for a Novel Antibiotic using Quantitative Systems Pharmacology Modeling

“…The full set of equations for DILIsym version 3A (and indeed for all versions of DILIsym past and present) is fully available to the members of the Initiative. Importantly, key equations from DILIsym have been published in the literature, including equations related to oxidative stress,5 bile acid homeostasis and transporter disruption,7, 9 mitochondrial dysfunction,10 and the dynamics of the innate immune system 11. These previous publications also provide significant insight into the scientific theory and knowledge behind the development of DILIsym.…”

“…Additional RNS/ROS can be generated by the parent drug or any of its metabolites according to a first‐order relationship. The generation of RNS/ROS disrupts the oxidative stress equilibrium resulting in RNS/ROS buildup in the hepatocytes 5. The RNS/ROS buildup leads to cellular apoptosis and necrosis; whether apoptosis or necrosis occurs depends on the extent of the RNS/ROS buildup and the presence of sufficient ATP inside the cell to complete the apoptotic process.…”

“…The basic DILIsym PBPK model framework consists of a compartmental model of the body with compartments for blood, gut, liver, muscle, and other tissues and has been described in previous publications 5, 8, 15. Because BAL30072 has been shown to be a substrate of organic anion transporter (OAT)1, OAT3, organic anion‐transporting polypeptide (OATP)1B1, and OATP1B3,4 the saturable liver uptake model was used for BAL30072.…”

“…Several in vitro assays can be used as inputs for DILIsym; thus, it is a useful tool for in vitro to in vivo extrapolation (IVIVE) and contextualizing these potentially predictive or explanatory in vitro assays. DILIsym has previously been used to predict and explain observed liver injury from various drugs using in vitro data inputs 5, 6, 7, 8. In this study, DILIsym version 3A was used in combination with previously reported in vitro toxicity data4 to predict the likelihood that oxidative stress generation and ETC inhibition observed in vitro can account for the observed elevations in serum ALT in the clinic.…”

10.5937/racter6-4032 = Xenobiotics-induced hepatotoxicity and an influence of HLA typisation

“…Утицај ХЛА ти-пизације код појединих врста ХТ може да по-могне у дијагностици и прогнози болести 21,42 . Биоинформатички приступ је такође ва-жан у дефинисању механизама имунских реакција, које су повезане са специфичним ХЛА типовима 43,44 . Данас је то омогућено на основу секвенчне ХЛА типизације, која по-стаје све бржа и јефтинија, а резултује у по-већаној доступности за појединца.…”