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This study aimed to develop a mechanistic model for assessing hyperbilirubinemia risk using genetic markers. We developed an ordinary differential equation (ODE)\u2010based mechanistic model of human bilirubin metabolism, incorporating key processes such as unconjugated bilirubin synthesis, hepatic uptake, conjugation to form conjugated bilirubin, and elimination via hepatic and renal pathways. The model includes key transporters and enzymes like OATP1B1, MRP2, MRP3, and UGT1A1 involved in bilirubin metabolism. The model was parametrized using in\u00a0vitro and published human data, validated in healthy subjects and genetic disease cases, and assessed for genetic mutations' impact on bilirubin levels. A 90% reduction in OATP1B1 enzymatic activity increased predicted unconjugated and conjugated bilirubin concentrations (1.58\u2010fold and 2.2\u2010fold, respectively), mimicking data from individuals with mutations in OATP1B1. Sensitivity analysis of OATP1B1, MRP2, and UGT1A1 revealed increased OATP1B1 sensitivity in the presence of low UGT1A1 activity. Model simulations linked nilotinib\u2010induced hyperbilirubinemia to UGT1A1 mutations, and simulations were used to assess the risk of hyperbilirubinemia associated with varying doses of nelfinavir, atazanavir, and TAK\u2010875, based on their off\u2010target effects on transporters. Results demonstrated that uncertainty in free drug tissue concentration may be crucial in hyperbilirubinemia, especially for highly protein\u2010bound drugs. This approach may help assess hyperbilirubinemia risk using a drug's inhibitory in\u00a0vitro data coupled with patient pharmacogenetic data for OATP1B1, UGT1A1, and MRP2 mutations.<\/jats:p>","DOI":"10.1002\/psp4.70037","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T17:27:34Z","timestamp":1772990854000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Risk Assessment for Drug\u2010Induced Hyperbilirubinemia: A Mechanistic Approach"],"prefix":"10.1002","volume":"15","author":[{"given":"Rajeev","family":"Kumar","sequence":"first","affiliation":[{"name":"Cellworks Group, Inc.  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ansu","family":"Kumar","sequence":"additional","affiliation":[{"name":"Cellworks Group, Inc.  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