ArticleToxicological sciences : an official journal of the Society of Toxicology2019
Quantitative Systems Toxicology Analysis of In Vitro Mechanistic Assays Reveals Importance of Bile Acid Accumulation and Mitochondrial Dysfunction in TAK-875-Induced Liver Injury.
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
20 citing papers in PubMed, 43 citations in OpenAlex.
- Hepatotoxicity of AKR1C3 Inhibitor BAY1128688: Findings from an Early Terminated Phase IIa Trial for the Treatment of Endometriosis.Drugs in R&D · 2023Trial
- Quantitative systems toxicology (QST) reproduces species differences in PF-04895162 liver safety due to combined mitochondrial and bile acid toxicity.Pharmacology research & perspectives · 2019Trial
- Phase I study of PF‐04895162, a Kv7 channel opener, reveals unexpected hepatotoxicity in healthy subjects, but not rats or monkeys: clinical evidence of disrupted bile acid homeostasis.Pharmacology research & perspectives · 2019Trial
- Quantitative Systems Toxicology Modeling with DILIsym to Support Phase 3 Dose Selection for Fezolinetant.Clinical pharmacology and therapeutics · 2026Article
- Risk Assessment for Drug-Induced Hyperbilirubinemia: A Mechanistic Approach.CPT: pharmacometrics & systems pharmacology · 2026Article
- Drug metabolizing enzymes and transporters, and their roles for the development of drug-induced liver injury.Expert opinion on drug metabolism & toxicology · 2025Review
- In vitro-in silico analysis reveals that loss of tankyrase1/2 improves bile acid handling in genetically engineered HepG2 cultures.Archives of toxicology · 2025Article
- 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.International journal of molecular sciences · 2023Article
- Comparing the Liver Safety Profiles of 4 Next-Generation CGRP Receptor Antagonists to the Hepatotoxic CGRP Inhibitor Telcagepant Using Quantitative Systems Toxicology Modeling.Toxicological sciences : an official journal of the Society of Toxicology · 2022Article
- Investigating bile acid-mediated cholestatic drug-induced liver injury using a mechanistic model of multidrug resistance protein 3 (MDR3) inhibition.Frontiers in pharmacology · 2022Article
- Preclinical models of idiosyncratic drug-induced liver injury (iDILI): Moving towards prediction.Acta pharmaceutica Sinica. B · 2021Review
- Human-relevant mechanisms and risk factors for TAK-875-Induced liver injury identified via a gene pathway-based approach in Collaborative Cross mice.Toxicology · 2021Article
- Targeting lipid GPCRs to treat type 2 diabetes mellitus - progress and challenges.Nature reviews. Endocrinology · 2021Review
- Evaluation of the hepatotoxicity of the novel GPR40 (FFAR1) agonist CPL207280 in the rat and monkey.PloS one · 2021Article
- The evolution of strategies to minimise the risk of human drug-induced liver injury (DILI) in drug discovery and development.Archives of toxicology · 2020Review
- Assessing Effects of BHV-0223 40 mg Zydis Sublingual Formulation and Riluzole 50 mg Oral Tablet on Liver Function Test Parameters Utilizing DILIsym.Toxicological sciences : an official journal of the Society of Toxicology · 2020Article
- Managing the challenge of drug-induced liver injury: a roadmap for the development and deployment of preclinical predictive models.Nature reviews. Drug discovery · 2020Review
- Comparison of the Hepatotoxic Potential of Two Treatments for Autosomal-Dominant Polycystic Kidney DiseaseUsing Quantitative Systems Toxicology Modeling.Pharmaceutical research · 2020Article
- The DILI-sim Initiative: Insights into Hepatotoxicity Mechanisms and Biomarker Interpretation.Clinical and translational science · 2019Review
- Molecular Biomarkers in Drug-Induced Liver Injury: Challenges and Future Perspectives.Frontiers in pharmacology · 2019Review
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
Abstract
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. Experimental data indicated that human bile salt export pump (BSEP) inhibition by TAK-875 was mixed whereas sodium taurocholate co-transporting polypeptide (NTCP) inhibition by TAK-875 was competitive. Furthermore, experimental data demonstrated that both TAK-875 and TAK-875-Glu inhibit mitochondrial electron transport chain (ETC) enzymes. These mechanistic data were combined with a physiologically based pharmacokinetic (PBPK) model constructed within DILIsym to estimate liver exposure of TAK-875 and TAK-875-Glu. In a simulated population (SimPops) constructed to reflect T2D patients, 16/245 (6.5%) simulated individuals developed alanine aminotransferase (ALT) elevations, an incidence similar to that observed with 200 mg daily dosing in clinical trials. Determining the mode of bile acid transporter inhibition (Ki) was critical to accurate predictions. In addition, simulations conducted on a sensitive subset of individuals (SimCohorts) revealed that when either BSEP or ETC inhibition was inactive, ALT elevations were not predicted to occur, suggesting that the two mechanisms operate synergistically to produce the observed clinical response. These results demonstrate how utilizing QST methods to interpret in vitro experimental results can lead to an improved understanding of the clinically relevant mechanisms underlying drug-induced toxicity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.