Approaches & Applications
Human-relevant experimental and computational approaches to drug safety, from cardiac effects to tissue-specific toxicity.
Follow research and regulatory developments concerning NAMs in drug safety assessment. This application collection brings together relevant cellular models, organoids, organ-on-chip systems and computational methods.
The emphasis is on the safety question and the evidence obtained: the exposure, measured endpoint, comparison and validation setting. Research findings, proposed regulatory approaches and established requirements retain their distinct status. Links lead to the underlying coverage and available method profiles.
A four-platform comparison combined lipid imaging, liver-function measurements, expression profiling and CYP assays. Lipid accumulation did not uniformly reduce drug metabolism, and differences depended on the model and donor.
Dendritic-cell/T-cell co-cultures and drug-specific clones revealed separate responses to mitiperstat and four metabolites. Most clone activation was consistent with direct pharmacological interaction.
A retrospective analysis of pharmaceutical regulatory data found better performance for Ames-test (Q)SAR models used in ICH M7 work than for models of mammalian-cell or in vivo genotoxicity. Reliability checks improved performance in some comparisons.
A medRxiv preprint simulated rosuvastatin exposure during ticagrelor coadministration in four age–ABCG2 genotype groups. Exposure-matching results differed by group, but the proposed dose scenarios were not clinically tested.
Researchers exposed human hippocampal organoids to valproic acid for four days, then profiled mRNA and miRNA. They found 19 altered miRNAs and tested selected target sequences in HEK-293T reporter cells, with limited replication from one iPSC line.
NIH researchers compared ADME@NCATS predictions with laboratory measurements for selected Tox21 compounds. Three basic ADME models reached ROC AUCs of 0.81–0.92; a separate passive blood–brain barrier model reached 0.77. The work supports compound triage, not validated prediction of in vivo toxicity.
Researchers exposed human cortical organoids to acetaminophen for five days and followed structural, transcriptomic and network outcomes for several months. Small early transcriptional changes did not translate into detectable differences in later cellular composition or the measured functional endpoints.
An academic kidney-toxicity model reached an AUC of 0.727 across 247 external compounds. Restricting the analysis to high- or medium-confidence predictions raised AUC to 0.902, but retained only 21.7% of that set.
A University of Vienna team compared chemical-structure, target and pathway fingerprints for drug-induced liver steatosis. Biological inputs performed better during internal validation, while accuracy fell on less-similar compounds and a separate 19-drug set.
Semaglutide partly protected human forebrain organoids against the structural and metabolic effects of cholesterol stress. The response was more limited in older cultures, where some calcium activity measures improved without restoring tissue size or several disease-associated markers.
Cardiomyocytes derived from one CAV3 p.Ala46Thr carrier showed altered protein localization and irregular calcium transients. Fenoterol increased transient frequency, but the pattern remained less regular than in a relative's control cells.
A six-drug study combines human intestinal organoid injury, epithelial turnover and pharmacokinetic models. Accounting for local intestinal exposure improves agreement with reported clinical diarrhea for drugs whose plasma concentrations understate the modeled intestinal effect.
A platform built around a flexible microelectrode array and scoop-shaped well combines electrical recordings with video of tissue motion. Organoids from healthy donors and patients with Duchenne muscular dystrophy show different structural features and responses to hERG blockade.
Two hiPSC-derived proximal tubule models show how transporter localization relates to directional drug transport and inhibitor responses. Transport activity and longer-term cell viability do not necessarily favor the same model.
