title: Mechanisms underlying benign and reversible unconjugated hyperbilirubinemia observed with faldaprevir administration in hepatitis C virus patients.
abstract: 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.
authors.affiliation: Boehringer Ingelheim Pharma Inc., Ridgefield, Connecticut (R.S.S., Q.H., Y.L., L.P., K.M., S.O., M.E.T., J.O.S., D.T.); Boehringer Ingelheim Pharma GmbH&Co. KG, Biberach, Germany (G.G.S., G.N.); Boehringer Ingelheim Pharma GmbH, Ingelheim, Germany (W.O.B.); and Hôpital Beaujon and INSERM UMR773, Université Denis Diderot Paris 7, Paris, France (T.A.) rucha.sane@boehringer-ingelheim.com.
authors.forename: Rucha S
authors.initials: RS
authors.lastname: Sane
authors.affiliation: Boehringer Ingelheim Pharma Inc., Ridgefield, Connecticut (R.S.S., Q.H., Y.L., L.P., K.M., S.O., M.E.T., J.O.S., D.T.); Boehringer Ingelheim Pharma GmbH&Co. KG, Biberach, Germany (G.G.S., G.N.); Boehringer Ingelheim Pharma GmbH, Ingelheim, Germany (W.O.B.); and Hôpital Beaujon and INSERM UMR773, Université Denis Diderot Paris 7, Paris, France (T.A.).
authors.forename: Gerhard G
authors.initials: GG
authors.lastname: Steinmann
authors.affiliation: Boehringer Ingelheim Pharma Inc., Ridgefield, Connecticut (R.S.S., Q.H., Y.L., L.P., K.M., S.O., M.E.T., J.O.S., D.T.); Boehringer Ingelheim Pharma GmbH&Co. KG, Biberach, Germany (G.G.S., G.N.); Boehringer Ingelheim Pharma GmbH, Ingelheim, Germany (W.O.B.); and Hôpital Beaujon and INSERM UMR773, Université Denis Diderot Paris 7, Paris, France (T.A.).
authors.forename: Qihong
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Boehringer Ingelheim Pharma Inc., Ridgefield, Connecticut (R.S.S., Q.H., Y.L., L.P., K.M., S.O., M.E.T., J.O.S., D.T.); Boehringer Ingelheim Pharma GmbH&Co. KG, Biberach, Germany (G.G.S., G.N.); Boehringer Ingelheim Pharma GmbH, Ingelheim, Germany (W.O.B.); and Hôpital Beaujon and INSERM UMR773, Université Denis Diderot Paris 7, Paris, France (T.A.).
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Boehringer Ingelheim Pharma Inc., Ridgefield, Connecticut (R.S.S., Q.H., Y.L., L.P., K.M., S.O., M.E.T., J.O.S., D.T.); Boehringer Ingelheim Pharma GmbH&Co. KG, Biberach, Germany (G.G.S., G.N.); Boehringer Ingelheim Pharma GmbH, Ingelheim, Germany (W.O.B.); and Hôpital Beaujon and INSERM UMR773, Université Denis Diderot Paris 7, Paris, France (T.A.).
authors.forename: Lalitha
authors.initials: L
authors.lastname: Podila
authors.affiliation: Boehringer Ingelheim Pharma Inc., Ridgefield, Connecticut (R.S.S., Q.H., Y.L., L.P., K.M., S.O., M.E.T., J.O.S., D.T.); Boehringer Ingelheim Pharma GmbH&Co. KG, Biberach, Germany (G.G.S., G.N.); Boehringer Ingelheim Pharma GmbH, Ingelheim, Germany (W.O.B.); and Hôpital Beaujon and INSERM UMR773, Université Denis Diderot Paris 7, Paris, France (T.A.).
authors.forename: Kirsten
authors.initials: K
authors.lastname: Mease
authors.affiliation: Boehringer Ingelheim Pharma Inc., Ridgefield, Connecticut (R.S.S., Q.H., Y.L., L.P., K.M., S.O., M.E.T., J.O.S., D.T.); Boehringer Ingelheim Pharma GmbH&Co. KG, Biberach, Germany (G.G.S., G.N.); Boehringer Ingelheim Pharma GmbH, Ingelheim, Germany (W.O.B.); and Hôpital Beaujon and INSERM UMR773, Université Denis Diderot Paris 7, Paris, France (T.A.).
authors.forename: Stephen
authors.initials: S
authors.lastname: Olson
authors.affiliation: Boehringer Ingelheim Pharma Inc., Ridgefield, Connecticut (R.S.S., Q.H., Y.L., L.P., K.M., S.O., M.E.T., J.O.S., D.T.); Boehringer Ingelheim Pharma GmbH&Co. KG, Biberach, Germany (G.G.S., G.N.); Boehringer Ingelheim Pharma GmbH, Ingelheim, Germany (W.O.B.); and Hôpital Beaujon and INSERM UMR773, Université Denis Diderot Paris 7, Paris, France (T.A.).
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Taub
authors.affiliation: Boehringer Ingelheim Pharma Inc., Ridgefield, Connecticut (R.S.S., Q.H., Y.L., L.P., K.M., S.O., M.E.T., J.O.S., D.T.); Boehringer Ingelheim Pharma GmbH&Co. KG, Biberach, Germany (G.G.S., G.N.); Boehringer Ingelheim Pharma GmbH, Ingelheim, Germany (W.O.B.); and Hôpital Beaujon and INSERM UMR773, Université Denis Diderot Paris 7, Paris, France (T.A.).
authors.forename: Jerry O
authors.initials: JO
authors.lastname: Stern
authors.affiliation: Boehringer Ingelheim Pharma Inc., Ridgefield, Connecticut (R.S.S., Q.H., Y.L., L.P., K.M., S.O., M.E.T., J.O.S., D.T.); Boehringer Ingelheim Pharma GmbH&Co. KG, Biberach, Germany (G.G.S., G.N.); Boehringer Ingelheim Pharma GmbH, Ingelheim, Germany (W.O.B.); and Hôpital Beaujon and INSERM UMR773, Université Denis Diderot Paris 7, Paris, France (T.A.).
authors.forename: Gerhard
authors.initials: G
authors.lastname: Nehmiz
authors.affiliation: Boehringer Ingelheim Pharma Inc., Ridgefield, Connecticut (R.S.S., Q.H., Y.L., L.P., K.M., S.O., M.E.T., J.O.S., D.T.); Boehringer Ingelheim Pharma GmbH&Co. KG, Biberach, Germany (G.G.S., G.N.); Boehringer Ingelheim Pharma GmbH, Ingelheim, Germany (W.O.B.); and Hôpital Beaujon and INSERM UMR773, Université Denis Diderot Paris 7, Paris, France (T.A.).
authors.forename: Wulf O
authors.initials: WO
authors.lastname: Böcher
authors.affiliation: Boehringer Ingelheim Pharma Inc., Ridgefield, Connecticut (R.S.S., Q.H., Y.L., L.P., K.M., S.O., M.E.T., J.O.S., D.T.); Boehringer Ingelheim Pharma GmbH&Co. KG, Biberach, Germany (G.G.S., G.N.); Boehringer Ingelheim Pharma GmbH, Ingelheim, Germany (W.O.B.); and Hôpital Beaujon and INSERM UMR773, Université Denis Diderot Paris 7, Paris, France (T.A.).
authors.forename: Tarik
authors.initials: T
authors.lastname: Asselah
authors.affiliation: Boehringer Ingelheim Pharma Inc., Ridgefield, Connecticut (R.S.S., Q.H., Y.L., L.P., K.M., S.O., M.E.T., J.O.S., D.T.); Boehringer Ingelheim Pharma GmbH&Co. KG, Biberach, Germany (G.G.S., G.N.); Boehringer Ingelheim Pharma GmbH, Ingelheim, Germany (W.O.B.); and Hôpital Beaujon and INSERM UMR773, Université Denis Diderot Paris 7, Paris, France (T.A.).
authors.forename: Donald
authors.initials: D
authors.lastname: Tweedie
mesh_terms: D000621:Aminoisobutyric Acids; D000818:Animals; D001663:Bilirubin / Q000378:metabolism; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004311:Double-Blind Method; D014453:Glucuronosyltransferase / Q000235:genetics; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D006801:Humans; D006932:Hyperbilirubinemia / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D007930:Leucine / Q000031:analogs & derivatives; D008099:Liver / Q000187:drug effects / Q000821:virology; D008253:Macaca mulatta; D015337:Multicenter Studies as Topic; D000089762:Multidrug Resistance-Associated Protein 2; D009842:Oligopeptides / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D011392:Proline / Q000031:analogs & derivatives; D011804:Quinolines; D016032:Randomized Controlled Trials as Topic; D051381:Rats; D013844:Thiazoles / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D000099148:UGT1A1 Enzyme
chemical_list: D000621:Aminoisobutyric Acids; D001663:Bilirubin; D014453:Glucuronosyltransferase; D007930:Leucine; D000089762:Multidrug Resistance-Associated Protein 2; D009842:Oligopeptides; D011392:Proline; D011804:Quinolines; D013844:Thiazoles; D000099148:UGT1A1 Enzyme; C000715087:ABCC2 protein, human; C552340:faldaprevir