Mechanistic Modeling Predicts Drug-Induced HyperbilirubinemiaThat Involves Inhibition Of Enzymes And Transporters
Elevated serum ALT and bilirubin indicates high risk of fatal drug-induced liver injury. However, drugs also can increase serum bilirubin in the absence of hepatic injury by inhibiting enzymes and/or transporters. The bilirubin sub-model within DILIsym® (the product of a public-private partnership involving scientists from industry, academia, and the FDA) was updated to predict drug-induced hyperbilirubinemia. METHODS: The bilirubin sub-model was optimized to bilirubin levels in patients with inherited disorders of bilirubin disposition: Rotor syndrome (RS), Gilbert syndrome (GS), and Dubin-Johnson syndrome (DJS). Indinavir (INV)-mediated hyperbilirubinemia was simulated using an INV PBPK model and its inhibition constants for UGT1A1 (6.8 μM) and OATP1B1 (4.1 μM). RESULTS: Simulations recapitulated conjugated hyperbilirubinemia in RS/DJS and unconjugated hyperbilirubinemia in GS [serum total bilirubin (TB): 2-7, 5-12, and 2-13 mg/dL, respectively]. After administration of 800 mg INV TID for 1 month, simulations predicted unconjugated hyperbilirubinemia (pre- and post-treatment serum TB: 0.55 and 0.69 mg/dL), which is consistent with reported clinical data (pre- and post-treatment serum TB: 0.5±0.28 and 0.84±0.36 mg/dL). CONCLUSION: Mechanistic modeling of bilirubin can be used to predict drug-induced hyperbilirubinemia, which is not related to liver injury.
American Society of Clinical Pharmacology (ASCPT), 16th Annual Meeting, March 9 – March 11, 2016, San Diego, CA
By Kyunghee Yang, Jeffrey L Woodhead, Paul B Watkins, Scott Q Siler, and Brett A Howell