Risk Assessment for Drug-Induced Hyperbilirubinemia: A Mechanistic Approach.

Hyperbilirubinemia, characterized by elevated total blood bilirubin levels including both unconjugated and conjugated forms, serves as a diagnostic marker for drug-induced liver toxicity associated with a wide range of medications. This study aimed to develop a mechanistic model for assessing hyperbilirubinemia risk using genetic markers. We developed an ordinary differential equation (ODE)-based 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 vitro 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-fold and 2.2-fold, 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-induced hyperbilirubinemia to UGT1A1 mutations, and simulations were used to assess the risk of hyperbilirubinemia associated with varying doses of nelfinavir, atazanavir, and TAK-875, based on their off-target effects on transporters. Results demonstrated that uncertainty in free drug tissue concentration may be crucial in hyperbilirubinemia, especially for highly protein-bound drugs. This approach may help assess hyperbilirubinemia risk using a drug's inhibitory in vitro data coupled with patient pharmacogenetic data for OATP1B1, UGT1A1, and MRP2 mutations.