Professor David Back

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2 THIRD JOINT CONFERENCE OF BHIVA AND BASHH 2014 Professor David Back University of Liverpool 1-4 April 2014, Arena and Convention Centre Liverpool

3 THIRD JOINT CONFERENCE OF BHIVA AND BASHH 2014 Professor David Back University of Liverpool COMPETING INTEREST OF FINANCIAL VALUE > 1,000: Speaker Name Prof David Back Statement Acts in a Consultancy capacity for Abbvie and as a speaker at company sponsored events for Gilead, Merck, Janssen, Viiv. Grant support for research and educational activities received from Gilead, Merck, Janssen, Viiv, Boehringer-Ingelheim, BMS. Date April April 2014, Arena and Convention Centre Liverpool

4 Slide 4 Managing the complexities of Pharmacology in HIV/HCV co-infected patients David Back University of Liverpool UK David Back, Liverpool Massimo Puoti, Milan Fiona Marra, Glasgow

5 Overview 1 Brief Introduction: David Back 2 3 Efficacy and Tolerability of DAAs in coinfected patients: Massimo Puoti Case-based Discussion: Fiona Marra; Massimo Puoti 4 Conclusions OTC: over the counter

6 HCV DAAs: a success story of multiple disciplines. Molecular Virology Deciphered the viral replication cycle and identified druggable targets. Structural Biology Provided high-resolution structures of viral targets such as NS3, NS5A and NS5B allowing modelling of drugtarget interactions 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.

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8 Treatment of HIV/HCV co-infected patients requires awareness and attention to the complex drug interactions that can occur between DAA and HIV antiretroviral medications.

9 Anti-HCV drugs approved and in advanced development Manns M & van Hahn Nature Rev Drug Discovery, 2013; 12:

10 The Changing Landscape ?

11 DAAs: Approved or Drug Metabolism Transporters Telaprevir Boceprevir Simeprevir Sofosbuvir Metabolised by CYP3A4 Inhibits CYP3A4 Metabolised by CYP3A4; AKR Inhibits CYP3A4 Metabolised by CYP3A4 Inhibits intestinal (not hepatic) CYP3A4 Metabolised by cathepsin A; CES1. Not metabolised by or inhibits CYPs Transported by P-gp Inhibits P-gp; OATP1B1/2 Transported by P-gp; BCRP Inhibits P-gp; OCT1/2 Tranported by P-gp Mild inhibitor of intestinal P-gp Inhibits OATP1B1, MRP2 Transported by P-gp and BCRP Inhibition (weak) of intestinal P-gp; BCRP Interaction Risk High High Moderate Low Kessara C et al 18 th CROI, Abs 118; Garg V et al 18 th CROI, Abs 629; Telaprevir SmPC, 2013; Boceprevir SmPC, 2013; Kiser JJ et al Hepatology 2012; 55: ; Kunze A et al Biochem Pharmacol 2012; 84: FDA Antiviral Drugs Advisory Committee Meeting Briefing Document: Simeprevir, October 2013; Simeprevir USPI; Sekar V et al; EASL 2010; Abstract 1076; Mathias A 14 th Int Workshop on Clin Pharm of HIV Ther; April 2013; Sofosbuvir USPI.

12 DAAs: Approved or Drug Metabolism Transporters Telaprevir Boceprevir Simeprevir Sofosbuvir Metabolised by CYP3A4 Inhibits CYP3A4 Metabolised by CYP3A4; AKR Inhibits CYP3A4 Metabolised by CYP3A4 Inhibits intestinal (not hepatic) CYP3A4 Metabolised by cathepsin A; CES1. Not metabolised by or inhibits CYPs Transported by P-gp Inhibits P-gp; OATP1B1/2 Transported by P-gp; BCRP Inhibits P-gp; OCT1/2 Tranported by P-gp Mild inhibitor of intestinal P-gp Inhibits OATP1B1, MRP2 Transported by P-gp and BCRP Inhibition (weak) of intestinal P-gp; BCRP Interaction Risk High High Moderate Low Kessara C et al 18 th CROI, Abs 118; Garg V et al 18 th CROI, Abs 629; Telaprevir SmPC, 2013; Boceprevir SmPC, 2013; Kiser JJ et al Hepatology 2012; 55: ; Kunze A et al Biochem Pharmacol 2012; 84: FDA Antiviral Drugs Advisory Committee Meeting Briefing Document: Simeprevir, October 2013; Simeprevir USPI; Sekar V et al; EASL 2010; Abstract 1076; Mathias A 14 th Int Workshop on Clin Pharm of HIV Ther; April 2013; Sofosbuvir USPI.

13 Slide 13 Perpetrator DAA ARV or co-med Victim

14 Antiretrovirals and Interaction Potential High Risk Medium Risk Lower/Low Risk Boosted PIs Perpetrators enzyme and transporter Inhibition Rilpivirine Victim of enzyme inhibition and induction. Also absorption. Dolutegravir Victim of enzyme induction and absorption interactions. EVG/cobi Perpetrators enzyme and transporter inhibition Maraviroc Victim of enzyme inhibition and induction. Raltegravir Victim of few induction and absorption interactions Efavirenz, nevirapine, etravirine Perpetrators enzyme and transporter induction Most NRTIs

15 Slide 15 Perpetrator ARV DAA or co-med Victim

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18 Finally Slide 18

19 Faldaprevir Metabolised by CYP3A4 Transported by P-gp, OATP1B1, MRP2 (Victim) Inhibition of CYP3A4 (at high dose) Inhibition of UGT1A1 Probable inhibition of OATP1B1, MRP2 (Perpetrator)

20 Faldaprevir and Bilirubin Disposition Faldaprevir is associated with hyperbilirubinemia largely due to unconjugated BIL Sane R et al J Hepatology 2011; 54 (Suppl 1) S488

21 Interaction of Faldaprevir (FDV) and ARVs Drug Effect of ARV on FDV AUC Victim Effect of FDV on ARV AUC Perpetrator Mechanism/ Recommendation Darunavir/r 2.29-fold increase 15% increase (Healthy) but 50% decrease (HIV-HCV) RTV Inhibits CYP3A4 Use FDV at 120 mg/day Atazanavir/r 2.19-fold increase No effect (HIV-HCV) RTV Inhibits CYP3A4 Use FDV at 120 mg/day Efavirenz 35% decrease 16% increase (Healthy) EFV induces CYP3A4 Use FDV at 240 mg/day Raltegravir No effect 2.7-fold increase (Healthy) FDV likely inhibits P-gp Tenofovir 22% decrease 22% increase (Healthy) Intestinal/renal transport No dose adjustment Sabo J et al ICCA 2012; Sabo J et al CROI 2013; Nelson M et al CROI 2014; Abs 499; Rockstroh J et al CROI 2014; Abs 497; Joseph D et al; CROI 2014; Abs 501

22 Daclatasvir Metabolised by CYP3A4 Transported by P-gp (Victim) Inhibits P-gp and OATP1B1 (Perpetrator)

23 Effect of Co-adminstered drugs on Daclatasvir: Victim Drug Effect on Daclatasvir Recommendation Atazanavir/r DCV AUC increased 2.1-fold DCV Cmin increased 3.6-fold Decrease dose to 30mg Efavirenz DCV AUC decreased 32% DCV Cmin decreased 59% Increase dose to 90 mg Tenofovir No effect No dose adjustment Omeprazole DCV AUC decreased 18% No dose adjustment Bifano M et al 2013; 18: ; Bifano M et al; 2013;EASL Abs 794.;

24 Drug Effect of Daclatasvir on Co-meds: Perpetrator Effect of Daclatasvir on co-med Recommendation Sofosbuvir SOF AUC increased 35%; GS no effect No dose adjustment Midazolam MDZ AUC decreased 13% No dose adjustment Cyclosporine No effect on CsA No dose adjustment Tacrolimus Oral Contraceptive No effect on TAC No effect on EE; Norgestrel AUC increased 12% No dose adjustment No dose adjustment Eley T et al th IWCPHepTHer Abs O-14; Eley T et al th IWCPHepTHer Abs O-15; Bifano M et al, CROI 2014; Abs 502; Bifano M et al 2011; 62nd AASLD; ABS 1340.

25 DAAs in Development Drug CYP Activity Transporters Interaction Potential Ledipasvir Little metabolism Not Inhibitor of CYP or UGT Not Inducer of CYP or UGT Asunaprevir Metabolised by CYP3A4 Induces CYP3A4 (weak) Inhibits CYP2D6 (weak) Transported by P-gp (likely) Inhibits intestinal P-gp (weak) Inhibits OATP1B1/3 (weak) Transported by P-gp, OATP1B1/3 Inhibits P-gp (weak), OATP1B1/3 Weak Moderate Eley T et al, 2013, 8 th Int Workshop on Clin Pharm of Hep Ther; Abs O-13; Eley T et al, 2011, 62 nd AASLD Abs 381; Eley T et al 2012, 7 th Int Workshop on Clin Pharm of Hep Ther; Abs O-4; Kirby B et al 2013, 8 th Int Workshop on Clin Pharm of Hep Ther; Abs O-20; Mathias A, 14 th Int Workshop on Clin Pharm of HIV Ther, Session 5

26 Abbvie 3D (ABT-450/r; ABT-267; ABT-333) Drug CYP/enzyme Activity Transporters Interaction Potential ABT-450 Metabolised by CYP3A4 Inhibits CYP2C8 Inhibits UGT1A1 Transported by P-gp, OATP1B1 Inhibits OATP1B1 and OATP1B3 High ABT-267 Metabolised by CYP3A4 Inhibits CYP2C8 Inhibits UGT1A1 ABT-333 Metabolised by CYP2C8 > CYP3A4 > CYP2D6 Inhibits UGT1A1 Transported by P-gp Transported by P-gp Inhibits OATP1B1 Moderate Moderate Abbvie Personal Communication

27 Merck drugs (MK-5172 and MK-8742) Drug CYP/enzyme Activity Transporters Interaction Potential MK-5172 Metabolised by CYP3A4 Inhibits (weak) CYP3A4 Inhibits CYP2C8 Inhibits UGT1A1 (weak) Transported by P-gp & OATP1B1 Inhibits BCRP? Moderate MK-8742 Metabolised by CYP3A4 Does not Inhibit CYP3A4 Inhibits UGT1A1 (weak) Transported by P-gp Transported by OATP1B1 (?) Moderate Yeh WW, HEP Dart 2013; Abs 52; Yeh WW et al CROI 2014, Abs 498 & Abs 638.

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30 Faldaprevir Drug Interactions: Perpetrator Faldaprevir showed moderate inhibition of CYP3A4 and weak inhibition of CYP2C9 and 2C19. Sabo J et al ICAAC 2012; A-1248

31 DAAs in Development Drug CYP/enzyme Activity Transporters Interaction Potential Faldaprevir Metabolised by CYP3A4 Inhibits CYP3A4 (240 mg dose) Inhibits CYP2C9 (240 mg dose) Inhibits UGT1A1 Transported by P-gp, MRP2, OATP1B1 Probable inhibitor of OATP1B1/3; MRP2 Moderate Daclatasvir Metabolised by CYP3A4 Does not inhibit major CYPs Transported by P-gp Inhibits OATP1B1; P-gp Moderate Kort J 2013; 14 th Int Workshop on Clin Pharm of HIV Ther, Session 5; Sane R et al 2011, 46 th EASL, Abs 1236; Sabo JP et al, 52 nd ICAAC, Abs A-1248; Bertz R 2013; 14 th Int Workshop on Clin Pharm of HIV Ther, Session 5; Bifano M et al, 2013, 8 th Int Workshop on Clin Pharm of Hep Ther, Abs O-15; Amblard F et al; Bioorg Med Chem Lett 23;

32 Note Ritonavir has effects on multiple enzymes and transporters. Formal drug interaction studies performed with either the 3-DAA regimen or the 2- DAA combination of ABT-450/r + ABT-333

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