Elucidating Differences in the Hepatotoxic Potential of Tolcapone and Entacapone With DILIsym ^® , a Mechanistic Model of Drug‐Induced Liver Injury

Abstract

Tolcapone and entacapone are catechol‐O‐methyltransferase (COMT) inhibitors developed as adjunct therapies for treating Parkinson's disease. While both drugs have been shown to cause mitochondrial dysfunction and inhibition of the bile salt export protein (BSEP), liver injury has only been associated with the use of tolcapone. Here we used a multiscale, mechanistic model (DILIsym®) to simulate the response to tolcapone and entacapone. In a simulated population (SimPops™) receiving recommended doses of tolcapone (200 mg t.i.d.), increases in serum alanine transaminase (ALT) >3× the upper limit of normal (ULN) were observed in 2.2% of the population. In contrast, no simulated patients receiving recommended doses of entacapone (200 mg 8× day) experienced serum ALT >3× ULN. Further, DILIsym® analyses revealed patient‐specific risk factors that may contribute to tolcapone‐mediated hepatotoxicity. In summary, the simulations demonstrated that differences in mitochondrial uncoupling potency and hepatic exposure primarily account for the difference in hepatotoxic potential for tolcapone and entacapone.

Application of a Mechanistic Model to Evaluate Putative Mechanisms of Tolvaptan Drug-Induced Liver Injury and Identify Patient Susceptibility Factors

“…Whereas the etiology of DILI events is rarely known, several putative mechanisms have been identified. For example, it has been demonstrated that compounds that inhibit the bile salt export pump (BSEP), a hepatic bile acid efflux transporter, are disproportionately represented amongst compounds with DILI liability (Morgan et al , 2010). The association between compounds that inhibit hepatic transporters and liver safety liabilities is strengthened further by considering compound inhibition of multidrug resistance-associated proteins (MRPs) (Morgan et al , 2013).…”

Mechanistic Modelling of Drug-Induced Liver Injury: Investigating the Role of Innate Immune Responses

“…Thus, compounds that induce hepatocyte necrosis via reactive metabolite, oxidative stress, bile acid accumulation, and/or mitochondrial dysfunction, all have the potential to induce an innate immune response. The successful simulation of hepatotoxicity due to compounds not used to optimize immune parameters15,18 provides indirect support that the immune system representation is reasonable within the whole DILI context. These other compounds also provide the opportunity to design experiments to test for the predicted innate immune response.…”

Quantitative systems toxicology (QST) reproduces species differences in PF‐04895162 liver safety due to combined mitochondrial and bile acid toxicity

“…This software integrates multiple submodels (eg , hepatocyte life cycle, mitochondrial dysfunction and toxicity, bile acid disposition, and biomarker release) into a single simulation. DILIsym also allows for a PBPK representation of drug metabolism and disposition, which have been described previously . The DILIsym software has been developed by the DILI‐sim Initiative, which is a public‐private partnership among scientists in academia, industry, and the US FDA .…”