Faldaprevir, an investigational agent for hepatitis C virus treatment, is well 
tolerated but associated with rapidly reversible, dose-dependent, clinically 
benign, unconjugated hyperbilirubinemia. Multidisciplinary preclinical and 
clinical studies were used to characterize mechanisms underlying this 
hyperbilirubinemia. In vitro, faldaprevir inhibited key processes involved in 
bilirubin clearance: UDP glucuronosyltransferase (UGT) 1A1 (UGT1A1) (IC50 0.45 
µM), which conjugates bilirubin, and hepatic uptake and efflux transporters, 
organic anion-transporting polypeptide (OATP) 1B1 (IC50 0.57 µM), OATP1B3 (IC50 
0.18 µM), and multidrug resistance-associated protein (MRP) 2 (IC50 6.2 µM), 
which transport bilirubin and its conjugates. In rat and human hepatocytes, 
uptake and biliary excretion of [(3)H]bilirubin and/or its glucuronides 
decreased on coincubation with faldaprevir. In monkeys, faldaprevir (≥20 mg/kg 
per day) caused reversible unconjugated hyperbilirubinemia, without hemolysis or 
hepatotoxicity. In clinical studies, faldaprevir-mediated hyperbilirubinemia was 
predominantly unconjugated, and levels of unconjugated bilirubin correlated with 
the UGT1A1*28 genotype. The reversible and dose-dependent nature of the clinical 
hyperbilirubinemia was consistent with competitive inhibition of bilirubin 
clearance by faldaprevir, and was not associated with liver toxicity or other 
adverse events. Overall, the reversible, unconjugated hyperbilirubinemia 
associated with faldaprevir may predominantly result from inhibition of 
bilirubin conjugation by UGT1A1, with inhibition of hepatic uptake of bilirubin 
also potentially playing a role. Since OATP1B1/1B3 are known to be involved in 
hepatic uptake of circulating bilirubin glucuronides, inhibition of OATP1B1/1B3 
and MRP2 may underlie isolated increases in conjugated bilirubin. As such, 
faldaprevir-mediated hyperbilirubinemia is not associated with any liver injury 
or toxicity, and is considered to result from decreased bilirubin elimination 
due to a drug-bilirubin interaction.