Key  Issues  in  Drug  Interac0ons  in  the   DAA  Era.   David  Back  -­‐  Liverpool,  UK Disclosures   •  Honoraria  received  from  Gilead,  Janssen,   Merck,  Abbvie,  BMS,  Boehringer-­‐Ingelheim,   Viiv.   •  Research  or  EducaConal  Grant  support  from   Gilead,  Janssen,  Merck,  Abbvie,  Roche,  Vertex,   BMS,  Boehringer-­‐Ingelheim,  Viiv.   •  PresentaCon  refers  to  the  following   unlabelled/unapproved  drugs:  faldaprevir,   daclatasvir,  asunaprevir,  ledipasvir,  ABT-­‐450/r,   ABT-­‐267,  ABT-­‐333;  MK-­‐5172,  MK-­‐8742. HCV DAAs: a success story of multiple disciplines. Ø  Molecular Virology Deciphered the viral replication cycle and identified druggable targets. Ø  Structural Biology Provided high-resolution structures of viral targets such as NS3, NS5A and NS5B – allowing modelling of drug- target interactions Ø  Molecular & Clinical Pharmacology Shown the disposition profiles of the compounds and helped develop strategies to optimise therapies – in particular in relation to drug-drug interactions. Anti-HCV drugs approved and in advanced development Manns M & van Hahn Nature Rev Drug Discovery, 2013; 12: 595-610 Direct Acting Antivirals against HCV Drug- Drug Interactions Toxicity Co- DAA med* Concentration Concentration of DAA of Co-med Reduced Efficacy * The Co-med may be an antiretroviral Perpetrator Co- DAA med Victim 1st Generation DAAs Telaprevir and Boceprevir Statement  from  Page  20  of  www.hcvguidelines.org Telaprevir and Boceprevir Interactions: What have we learned? Non-CYP Drug CYP 3A4 Transporters metabolism §  Transported by P-gp §  Metabolised by Telaprevir §  Inhibits P-gp; – §  Inhibits OATP1B1/2 §  Transported by P-gp; AKR §  Metabolised by Boceprevir BCRP §  Metabolised §  Inhibits §  Inhibits P-gp; OCT1/2 by CYP 3A isozymes are §  The most abundant CYP enzymes in the liver §  Involved in the metabolism of many drugs P-gp: P-glycoprotein; AKR: aldo-keto reductase Kessara C et al 18th CROI, Abs 118; Garg V et al 18th CROI, Abs 629; Telaprevir SmPC, 2013; Boceprevir SmPC, 2013; Kiser JJ et al Hepatology 2012; 55: 1620-1628; Kunze A et al Biochem Pharmacol 2012; 84: 1096-1102. Slide 10 Importance of metabolism and transport in relation to systemic drug levels drug   Ø  Dissolution Hepatocytes   Ø  Food effects 100%   UGTs   Ø Enzyme induction/inhibition Ø Transporter induction/ CYP3A4   inhibition Enterocytes   2   OATP1A2   OATP1B1   OATP2B1   OATP1B3   OCT1   CYP 2A6 CYP 2B6 CYP3A4   1   CYP 2C8 CYP 1A2 P-­‐gp   CYP 2C9 BCRP   CYP 2C19 MRP2   CYP 2D6 CYP 3A CYP 2E1 Adapted from: Bailey DG, et al. CMAJ 2013;185:1066