Prediction of the liver safety profile of a first-in-class myeloperoxidase inhibitor using quantitative systems toxicology modeling.

The novel myeloperoxidase inhibitor verdiperstat was developed as a treatment for neuroinflammatory and neurodegenerative diseases. During development, a computational prediction of verdiperstat liver safety was performed using DILIsym v8A, a quantitative systems toxicology (QST) model of liver safety.A physiologically-based pharmacokinetic (PBPK) model of verdiperstat was constructed in GastroPlus 9.

Quantitative Systems Toxicology Modeling Informed Safe Dose Selection of Emvododstat in Acute Myeloid Leukemia Patients.

Clinical investigation of emvododstat for the treatment of solid tumors was halted after two patients who were heavily treated with other anticancer therapies experienced drug-induced liver failure. However, preclinical investigations supported that emvododstat at lower doses might be effective in treating acute myeloid leukemia (AML) and against severe acute respiratory syndrome-coronavirus 2 as a dihydroorotate dehydrogenase inhibitor. Therefore, a quantitative systems toxicology model, DILIsym, was used to predict liver safety of the proposed dosing of emvododstat in AML clinical trials.

Assessing Liver Effects of Cannabidiol and Valproate Alone and in Combination Using Quantitative Systems Toxicology.

In clinical trials of cannabidiol (CBD) for the treatment of seizures in patients with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex, elevations in serum alanine aminotransferase (ALT) > 3× the upper limit of normal were observed in some patents, but the incidence was much greater in patients who were receiving treatment with valproate (VPA) before starting CBD. To explore potential mechanisms underlying this interaction, we used DILIsym, a quantitative systems toxicology model, to predict ALT elevations in a simulated human population treated with CBD alone, VPA alone, and when CBD dosing was starting during treatment with VPA. We gathered in vitro data assessing the potential for CBD, the two major CBD metabolites, and VPA to cause hepatotoxicity via inhibition of bile acid transporters, mitochondrial dysfunction, and production of reactive oxygen species (ROS).

The Combination of a Human Biomimetic Liver Microphysiology System with BIOLOGXsym, a Quantitative Systems Toxicology (QST) Modeling Platform for Macromolecules, Provides Mechanistic Understanding of Tocilizumab- and GGF2-Induced Liver Injury.

Biologics address a range of unmet clinical needs, but the occurrence of biologics-induced liver injury remains a major challenge. Development of cimaglermin alfa (GGF2) was terminated due to transient elevations in serum aminotransferases and total bilirubin. Tocilizumab has been reported to induce transient aminotransferase elevations, requiring frequent monitoring.

Mechanistic investigation of liver injury induced by BMS-932481, an experimental ɣ-secretase modulator.

BMS-932481 was designed to modulate ɣ-secretase activity to produce shorter and less amyloidogenic peptides, potentially averting liabilities associated with complete enzymatic inhibition. Although it demonstrated the intended pharmacology in the clinic, BMS-932481 unexpectedly caused drug-induced liver injury (DILI) in a multiple ascending dose study characterized by dose- and exposure-dependence, delayed onset manifestation, and a high incidence of hepatocellular damage. Retrospective studies investigating the disposition and probable mechanisms of toxicity of BMS-932481 are presented here.

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

Inhibition of the canalicular phospholipid floppase multidrug resistance protein 3 (MDR3) has been implicated in cholestatic drug-induced liver injury (DILI), which is clinically characterized by disrupted bile flow and damage to the biliary epithelium. Reduction in phospholipid excretion, as a consequence of MDR3 inhibition, decreases the formation of mixed micelles consisting of bile acids and phospholipids in the bile duct, resulting in a surplus of free bile acids that can damage the bile duct epithelial cells, i.e.

Application of the DILIsym® Quantitative Systems Toxicology drug-induced liver injury model to evaluate the carcinogenic hazard potential of acetaminophen.

In 2019, the California Office of Environmental Health Hazard Assessment (OEHHA) initiated a review of the carcinogenic hazard potential of acetaminophen. The objective of the analysis herein was to inform this review by assessing whether variability in patient baseline characteristics (e.g.

Assessing Effects of BHV-0223 40 mg Zydis Sublingual Formulation and Riluzole 50 mg Oral Tablet on Liver Function Test Parameters Utilizing DILIsym.

For patients with amyotrophic lateral sclerosis who take oral riluzole tablets, approximately 50% experience alanine transaminase (ALT) levels above upper limit of normal (ULN), 8% above 3× ULN, and 2% above 5× ULN. BHV-0223 is a novel 40 mg rapidly sublingually disintegrating (Zydis) formulation of riluzole, bioequivalent to conventional riluzole 50 mg oral tablets, that averts the need for swallowing tablets and mitigates first-pass hepatic metabolism, thereby potentially reducing risk of liver toxicity. DILIsym is a validated multiscale computational model that supports evaluation of liver toxicity risks.

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

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).

Analyzing the Mechanisms Behind Macrolide Antibiotic-Induced Liver Injury Using Quantitative Systems Toxicology Modeling.

Purpose: Macrolide antibiotics are commonly prescribed treatments for drug-resistant bacterial infections; however, many macrolides have been shown to cause liver enzyme elevations and one macrolide, telithromycin, has been pulled from the market by its provider due to liver toxicity. This work seeks to assess the mechanisms responsible for the toxicity of macrolide antibiotics.

Methods: Five macrolides were assessed in in vitro systems designed to test for bile acid transporter inhibition, mitochondrial dysfunction, and oxidative stress.

Quantitative Systems Toxicology Analysis of In Vitro Mechanistic Assays Reveals Importance of Bile Acid Accumulation and Mitochondrial Dysfunction in TAK-875-Induced Liver Injury.

TAK-875 (fasiglifam), a GPR40 agonist in development for the treatment of type 2 diabetes (T2D), was voluntarily terminated in Phase III trials due to adverse liver effects. The potential mechanisms of TAK-875 toxicity were explored by combining in vitro experiments with quantitative systems toxicology (QST) using DILIsym, a mathematical representation of drug-induced liver injury. In vitro assays revealed that bile acid transporters were inhibited by both TAK-875 and its metabolite, TAK-875-Glu.

Using Quantitative Systems Toxicology to Investigate Observed Species Differences in CKA-Mediated Hepatotoxicity.

CKA, a chemokine receptor antagonist intended for treating inflammatory conditions, produced dose-dependent hepatotoxicity in rats but advanced into the clinic where single doses of CKA up to 600 mg appeared safe in humans. Because existing toxicological platforms used during drug development are not perfectly predictive, a quantitative systems toxicology model investigated the hepatotoxic potential of CKA in humans and rats through in vitro assessments of CKA on mitochondrial respiration, oxidative stress, and bile acid transporters. DILIsym predicted that single doses of CKA caused serum ALT >3xULN in a subset of the simulated rat population, while single doses in a simulated human population did not produce serum ALT elevations.

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

Elevations of liver enzymes have been observed in clinical trials with BAL30072, a novel antibiotic. In vitro assays have identified potential mechanisms for the observed hepatotoxicity, including electron transport chain (ETC) inhibition and reactive oxygen species (ROS) generation. DILIsym, a quantitative systems pharmacology (QSP) model of drug-induced liver injury, has been used to predict the likelihood that each mechanism explains the observed toxicity.

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

Drug-induced liver injury (DILI) remains an adverse event of significant concern for drug development and marketed drugs, and the field would benefit from better tools to identify liver liabilities early in development and/or to mitigate potential DILI risk in otherwise promising drugs. DILIsym software takes a quantitative systems toxicology approach to represent DILI in pre-clinical species and in humans for the mechanistic investigation of liver toxicity. In addition to multiple intrinsic mechanisms of hepatocyte toxicity (ie, oxidative stress, bile acid accumulation, mitochondrial dysfunction), DILIsym includes the interaction between hepatocytes and cells of the innate immune response in the amplification of liver injury and in liver regeneration.

The role of quantitative systems pharmacology modeling in the prediction and explanation of idiosyncratic drug-induced liver injury.

Idiosyncratic drug-induced liver injury (iDILI) is a serious concern in drug development. The rarity and multifactorial nature of iDILI makes it difficult to predict and explain. Recently, human leukocyte antigen (HLA) allele associations have provided strong support for a role of an adaptive immune response in the pathogenesis of many iDILI cases; however, it is likely that an adaptive immune attack requires several preceding events.

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

Tolvaptan is a selective vasopressin V2 receptor antagonist, approved in several countries for the treatment of hyponatremia and autosomal dominant polycystic kidney disease (ADPKD). No liver injury has been observed with tolvaptan treatment in healthy subjects and in non-ADPKD indications, but ADPKD clinical trials showed evidence of drug-induced liver injury (DILI). Although all DILI events resolved, additional monitoring in tolvaptan-treated ADPKD patients is required.

Sandwich-Cultured Hepatocytes as a Tool to Study Drug Disposition and Drug-Induced Liver Injury.

Sandwich-cultured hepatocytes (SCH) are metabolically competent and have proper localization of basolateral and canalicular transporters with functional bile networks. Therefore, this cellular model is a unique tool that can be used to estimate biliary excretion of compounds. SCH have been used widely to assess hepatobiliary disposition of endogenous and exogenous compounds and metabolites.

Exploring BSEP inhibition-mediated toxicity with a mechanistic model of drug-induced liver injury.

Inhibition of the bile salt export pump (BSEP) has been linked to incidence of drug-induced liver injury (DILI), presumably by the accumulation of toxic bile acids in the liver. We have previously constructed and validated a model of bile acid disposition within DILIsym®, a mechanistic model of DILI. In this paper, we use DILIsym® to simulate the DILI response of the hepatotoxic BSEP inhibitors bosentan and CP-724,714 and the non-hepatotoxic BSEP inhibitor telmisartan in humans in order to explore whether we can predict that hepatotoxic BSEP inhibitors can cause bile acid accumulation to reach toxic levels.

Use of a systems model of drug-induced liver injury (DILIsym(®)) to elucidate the mechanistic differences between acetaminophen and its less-toxic isomer, AMAP, in mice.

Acetaminophen (APAP) has been used as a probe drug to investigate drug-induced liver injury (DILI). In mice, 3'-hydroxyacetanilide (AMAP), a less-toxic isomer of APAP, has also been studied as a negative control. Various mechanisms for the divergence in toxicological response between the two isomers have been proposed.

Linking physiology to toxicity using DILIsym®, a mechanistic mathematical model of drug-induced liver injury.

The drug development industry faces multiple challenges in the realization of safe effective drugs. Computational modeling approaches can be used to support these efforts. One approach, mechanistic modeling, is new to the realm of drug safety.

Modeling drug- and chemical-induced hepatotoxicity with systems biology approaches.

We provide an overview of computational systems biology approaches as applied to the study of chemical- and drug-induced toxicity. The concept of "toxicity pathways" is described in the context of the 2007 US National Academies of Science report, "Toxicity testing in the 21st Century: A Vision and A Strategy." Pathway mapping and modeling based on network biology concepts are a key component of the vision laid out in this report for a more biologically based analysis of dose-response behavior and the safety of chemicals and drugs.

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

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.