title: Contribution of Major Metabolites toward Complex Drug-Drug Interactions of Deleobuvir: In Vitro Predictions and In Vivo Outcomes.
abstract: The drug-drug interaction (DDI) potential of deleobuvir, an hepatitis C virus (HCV) polymerase inhibitor, and its two major metabolites, CD 6168 (formed via reduction by gut bacteria) and deleobuvir-acyl glucuronide (AG), was assessed in vitro. Area-under-the-curve (AUC) ratios (AUCi/AUC) were predicted using a static model and compared with actual AUC ratios for probe substrates in a P450 cocktail of caffeine (CYP1A2), tolbutamide (CYP2C9), and midazolam (CYP3A4), administered before and after 8 days of deleobuvir administration to HCV-infected patients. In vitro studies assessed inhibition, inactivation and induction of P450s. Induction was assessed in a short-incubation (10 hours) hepatocyte assay, validated using positive controls, to circumvent cytotoxicity seen with deleobuvir and its metabolites. Overall, P450 isoforms were differentially affected by deleobuvir and its two metabolites. Of note was more potent CYP2C8 inactivation by deleobuvir-AG than deleobuvir and P450 induction by CD 6168 but not by deleobuvir. The predicted net AUC ratios for probe substrates were 2.92 (CYP1A2), 0.45 (CYP2C9), and 0.97 (CYP3A4) compared with clinically observed ratios of 1.64 (CYP1A2), 0.86 (CYP2C9), and 1.23 (CYP3A4). Predictions of DDI using deleobuvir alone would have significantly over-predicted the DDI potential for CYP3A4 inhibition (AUC ratio of 6.15). Including metabolite data brought the predicted net effect close to the observed DDI. However, the static model over-predicted the induction of CYP2C9 and inhibition/inactivation of CYP1A2. This multiple-perpetrator DDI scenario highlights the application of the static model for predicting complex DDI for CYP3A4 and exemplifies the importance of including key metabolites in an overall DDI assessment.
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (R.S.S, D.R., J.P.S., L.R., N.T., A.W.J, D.J.T) and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (C.C.) rucha.sane@boehringer-ingelheim.com.
authors.forename: Rucha S
authors.initials: RS
authors.lastname: Sane
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (R.S.S, D.R., J.P.S., L.R., N.T., A.W.J, D.J.T) and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (C.C.).
authors.forename: Diane
authors.initials: D
authors.lastname: Ramsden
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (R.S.S, D.R., J.P.S., L.R., N.T., A.W.J, D.J.T) and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (C.C.).
authors.forename: John P
authors.initials: JP
authors.lastname: Sabo
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (R.S.S, D.R., J.P.S., L.R., N.T., A.W.J, D.J.T) and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (C.C.).
authors.forename: Curtis
authors.initials: C
authors.lastname: Cooper
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (R.S.S, D.R., J.P.S., L.R., N.T., A.W.J, D.J.T) and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (C.C.).
authors.forename: Lois
authors.initials: L
authors.lastname: Rowland
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (R.S.S, D.R., J.P.S., L.R., N.T., A.W.J, D.J.T) and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (C.C.).
authors.forename: Naitee
authors.initials: N
authors.lastname: Ting
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (R.S.S, D.R., J.P.S., L.R., N.T., A.W.J, D.J.T) and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (C.C.).
authors.forename: Andrea
authors.initials: A
authors.lastname: Whitcher-Johnstone
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (R.S.S, D.R., J.P.S., L.R., N.T., A.W.J, D.J.T) and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (C.C.).
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Tweedie
mesh_terms: D000179:Acrylates / Q000378:metabolism*; D019540:Area Under Curve; D001562:Benzimidazoles / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions / Q000502:physiology*; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008297:Male
chemical_list: D000179:Acrylates; D001562:Benzimidazoles; D065692:Cytochrome P-450 CYP3A Inhibitors; C000592437:deleobuvir; D003577:Cytochrome P-450 Enzyme System