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

Abstract

Many compounds that appear promising in preclinical species, fail in human clinical trials due to safety concerns. The FDA has strongly encouraged the application of modeling in drug development to improve product safety. This study illustrates how DILIsym, a computational representation of liver injury, was able to reproduce species differences in liver toxicity due to PF‐04895162 (ICA‐105665). PF‐04895162, a drug in development for the treatment of epilepsy, was terminated after transaminase elevations were observed in healthy volunteers (NCT01691274). Liver safety concerns had not been raised in preclinical safety studies. DILIsym, which integrates in vitro data on mechanisms of hepatotoxicity with predicted in vivo liver exposure, reproduced clinical hepatotoxicity and the absence of hepatotoxicity observed in the rat. Simulated differences were multifactorial. Simulated liver exposure was greater in humans than rats. The simulated human hepatotoxicity was demonstrated to be due to the interaction between mitochondrial toxicity and bile acid transporter inhibition; elimination of either mechanism from the simulations abrogated injury. The bile acid contribution occurred despite the fact that the IC50 for bile salt export pump (BSEP) inhibition by PF‐04895162 was higher (311 µmol/L) than that has been generally thought to contribute to hepatotoxicity. Modeling even higher PF‐04895162 liver exposures than were measured in the rat safety studies aggravated mitochondrial toxicity but did not result in rat hepatotoxicity due to insufficient accumulation of cytotoxic bile acid species. This investigative study highlights the potential for combined in vitro and computational screening methods to identify latent hepatotoxic risks and paves the way for similar and prospective studies.

Investigating bile acid-mediated cholestatic drug-induced liver injury using a mechanistic model of multidrug resistance protein 3 (MDR3) inhibition

“…While competitive inhibition had a negligible impact on PL efflux ( Figure 7A ) and on downstream, biliary pathways ( Figures 7B–J ), non-competitive inhibition, and a wide spectrum of mixed inhibition scenarios did predict major disturbances in the bile duct. In the case of BA transporter inhibition, non-competitive and competitive inhibition types have shown to lead to high and low extremes of potential hepatocellular BA accumulation, respectively, whereas mixed inhibition with α = 5 represents a more balanced scenario that has been used when inhibition type is unknown ( Generaux et al, 2019 ; Woodhead et al, 2019 ). As a representative case for mixed inhibition of MDR3, α = 5 was selected to demonstrate the types of bile duct alterations that were predicted to occur ( Figure 7 ).…”

“…In the case of BA transporter inhibition, non-competitive and competitive inhibition types have shown to lead to high and low extremes of potential hepatocellular BA accumulation, respectively, whereas mixed inhibition with α = 5 represents a more balanced scenario that has been used when inhibition type is unknown (Generaux et al, 2019;Woodhead et al, 2019). As a representative case for mixed inhibition of MDR3, α = 5 was selected to demonstrate the types of bile duct alterations that were predicted to occur (Figure 7).…”

“…The modeling platform combines drug and metabolite exposure at the site of interaction with hepatotoxicity mechanisms to delineate the impact of these compounds, at specific concentrations, on the cellular, organ and whole organism levels ( Mosedale and Watkins, 2017 ). Various prospective and retrospective applications of DILIsym have provided support that DILI liability of a compound can be attributed to three key mechanisms: mitochondrial dysfunction, oxidative stress, and alterations in BA homeostasis ( Howell et al, 2012 ; Shoda et al, 2014 ; Longo et al, 2016 ; Mosedale and Watkins, 2017 ; Woodhead et al, 2018 ; 2020 ; 2022 ; Generaux et al, 2019 ). The present work describes the new cholestatic liver injury-related components that were incorporated into the model, which extends the original BA homeostasis model, and has the potential to improve the predictive capability of the DILIsym model as a whole.…”

Moving beyond Binary Predictions of Human Drug-Induced Liver Injury (DILI) toward Contrasting Relative Risk Potential

“…Both PF-04895162 and flupirtine are weak/modest BSEP inhibitors with mitochondrial inhibitory effects. These combined two properties can promote transaminase elevations in humans based on modeling PF‑04895162 in DILIsym . PF-06547136 was eventually evaluated for an alternative indication but was not found efficacious in an animal model and was discontinued.…”

Micropillar/Microwell Chip Assessment for Detoxification of Bisphenol A with Korean Pear (Pyrus pyrifolia)

“…Nonetheless, metabolism-induced toxicity of xenobiotics in the liver has been overlooked, which could be critical to determine potential human toxicity due to the significant discrepancy between animal and human metabolism in the liver. Many compounds that appear promising in preclinical species, fail in human clinical trials due to safety concerns [ 2 ]. In fact, metabolism is a double-sided knife, as xenobiotics can be biotransformed into inactive or bioactive intermediates by metabolic enzymes.…”