DIGITAL TWIN OF DRUG-INDUCED LIVER INJURY AND SYSTEMIC ADVERSE DRUG REACTIONS IN MASS MEDICATION SCENARIOS: PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELS

Abstract

The expansion of self-medication, broad over-the-counter drug availability, seasonal surges in symptomatic medication use, and polypharmacy have made drug-induced liver injury and systemic adverse drug reactions a problem of both clinical medicine and medicinal chemistry. The aim of this re-view is to propose a digital twin of DILI/ADR as an interpretable research platform integrating physiologically based pharmacokinetic models, mechanis-tic toxicity modules, and a panel of early liver injury biomarkers. The analysis shows that reliance on ALT/AST alone is insufficient for early detection of toxicity, particularly in the presence of comorbidity, steatotic liver disease, muscle injury, and polypharmacy. The roles of early and more specific markers – miR-122, GLDH, K18, bile acid profiles, acylcarnitines, and glutathione-related parameters – are discussed alongside conventional biochem-istry. Particular attention is given to the key mechanistic nodes of DILI: mitochondrial dysfunction, disturbed bile acid homeostasis along the BSEP ax-is, formation of reactive metabolites, and limitations of glutathione, glucuronidation, and sulfation capacity. Acetylsalicylic acid is used as an illustrative OTC case within a broader framework: its rapid hydrolysis to salicylate, saturable elimination, the involvement of glycine conjugation and glucuronida-tion, and pharmacokinetic variability with ageing, hypoalbuminemia, and liver disease make it a useful model for a digital twin of mass medication scenarios. The review concludes that combining PBPK models, mechanistic biomarkers, and targeted LC-MS/MS analytics may enable a transition from descriptive pharmacovigilance to quantitatively interpretable risk stratification and more focused monitoring in mass medication settings.