1-4 April 2014, Arena and Convention Centre Liverpool

THIRD JOINT CONFERENCE

OF BHIVA AND BASHH 2014

Professor David BackUniversity of Liverpool

1-4 April 2014, Arena and Convention Centre Liverpool

THIRD JOINT CONFERENCE

OF BHIVA AND BASHH 2014

Professor David BackUniversity of Liverpool

COMPETING INTEREST OF FINANCIAL VALUE > £1,000:

Speaker Name Statement

Prof David Back

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 2014

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

Overview

OTC: over the counter

Brief Introduction: David Back

Efficacy and Tolerability of DAAs in co-infected patients: Massimo Puoti

Case-based Discussion: Fiona Marra; Massimo Puoti

Conclusions

1

2

3

4

HCV DAAs: a success story of multiple

disciplines.

Molecular Virology

Deciphered the viral replication cycle and identified

druggable targets.

Structural BiologyProvided high-resolution structures of viral targets such

as NS3, NS5A and NS5B – allowing modelling of drug-

target interactions

Molecular & Clinical PharmacologyShown the disposition profiles of the compounds and

helped develop strategies to optimise therapies – in

particular in relation to drug-drug interactions.

‘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’.

Anti-HCV drugs approved and in

advanced development

Manns M & van Hahn Nature Rev Drug Discovery, 2013; 12: 595-610

The Changing Landscape

2013

2014?

Drug Metabolism Transporters

Interaction

Risk

Telaprevir Metabolised by

CYP3A4

Inhibits CYP3A4

Transported by P-gp

Inhibits P-gp; OATP1B1/2High

Boceprevir Metabolised by

CYP3A4; AKR

Inhibits CYP3A4

Transported by P-gp;

BCRP

Inhibits P-gp; OCT1/2

High

Simeprevir

Metabolised by

CYP3A4

Inhibits intestinal (not

hepatic) CYP3A4

Tranported by P-gp

Mild inhibitor of intestinal

P-gp

Inhibits OATP1B1, MRP2

Moderate

Sofosbuvir

Metabolised by

cathepsin A; CES1.

Not metabolised by or

inhibits CYPs

Transported by P-gp and

BCRP

Inhibition (weak) of

intestinal P-gp; BCRP

Low

DAAs: Approved or………

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. FDA Antiviral Drugs Advisory

Committee Meeting Briefing Document: Simeprevir, October 2013; Simeprevir USPI; Sekar V et al; EASL 2010; Abstract 1076;

Mathias A 14th Int Workshop on Clin Pharm of HIV Ther; April 2013; Sofosbuvir USPI.

Drug Metabolism Transporters

Interaction

Risk

Telaprevir Metabolised by

CYP3A4

Inhibits CYP3A4

Transported by P-gp

Inhibits P-gp; OATP1B1/2High

Boceprevir Metabolised by

CYP3A4; AKR

Inhibits CYP3A4

Transported by P-gp;

BCRP

Inhibits P-gp; OCT1/2

High

Simeprevir

Metabolised by

CYP3A4

Inhibits intestinal (not

hepatic) CYP3A4

Tranported by P-gp

Mild inhibitor of intestinal

P-gp

Inhibits OATP1B1, MRP2

Moderate

Sofosbuvir

Metabolised by

cathepsin A; CES1.

Not metabolised by or

inhibits CYPs

Transported by P-gp and

BCRP

Inhibition (weak) of

intestinal P-gp; BCRP

Low

DAAs: Approved or………

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. FDA Antiviral Drugs Advisory

Committee Meeting Briefing Document: Simeprevir, October 2013; Simeprevir USPI; Sekar V et al; EASL 2010; Abstract 1076;

Mathias A 14th Int Workshop on Clin Pharm of HIV Ther; April 2013; Sofosbuvir USPI.

Slide 13

DAAARV or

co-med

Perpetrator

Victim

High Risk Medium Risk Lower/Low Risk

Boosted PIsPerpetrators – enzyme

and transporter

Inhibition

RilpivirineVictim of enzyme

inhibition and induction.

Also absorption.

DolutegravirVictim of enzyme

induction and absorption

interactions.

EVG/cobiPerpetrators – enzyme

and transporter

inhibition

MaravirocVictim of enzyme

inhibition and induction.

RaltegravirVictim of few induction

and absorption

interactions

Efavirenz,

nevirapine,

etravirinePerpetrators – enzyme

and transporter

induction

Most NRTIs

Antiretrovirals and Interaction Potential

Slide 15

ARVDAA or

co-med

Perpetrator

Victim

Slide 17

Slide 18

Finally

Faldaprevir

Metabolised by CYP3A4

Transported by P-gp, OATP1B1, MRP2

(Victim)

Inhibition of CYP3A4 (at high dose)

Inhibition of UGT1A1Probable inhibition of OATP1B1, MRP2

(Perpetrator)

Faldaprevir and Bilirubin Disposition

Faldaprevir is associated with hyperbilirubinemia largely

due to unconjugated BILSane R et al J Hepatology 2011; 54 (Suppl 1) S488

Drug

Effect of ARV

on FDV AUC

Victim

Effect of FDV

on ARV AUC

Perpetrator

Mechanism/

Recommendation

Darunavir/r2.29-fold

increase

15% increase

(Healthy) but

50% decrease

(HIV-HCV)

RTV Inhibits CYP3A4

Use FDV at 120 mg/day

Atazanavir/r2.19-fold

increase

No effect

(HIV-HCV)

RTV Inhibits CYP3A4

Use FDV at 120 mg/day

Efavirenz 35% decrease16% increase

(Healthy)

EFV induces CYP3A4

Use FDV at 240 mg/day

Raltegravir No effect2.7-fold increase

(Healthy)FDV likely inhibits P-gp

Tenofovir 22% decrease22% 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

Interaction of Faldaprevir (FDV) and ARVs

Daclatasvir

Metabolised by CYP3A4

Transported by P-gp

(Victim)

Inhibits P-gp and OATP1B1

(Perpetrator)

Effect of Co-adminstered drugs on

Daclatasvir: Victim

Drug Effect on Daclatasvir Recommendation

Atazanavir/rDCV AUC increased 2.1-fold

DCV Cmin increased 3.6-foldDecrease dose to 30mg

EfavirenzDCV 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: 931-941; Bifano M et al; 2013;EASL Abs 794.;

Effect of Daclatasvir on Co-meds:

Perpetrator

DrugEffect of Daclatasvir on

co-medRecommendation

SofosbuvirSOF AUC increased 35%;

GS-331007 – no effect

No dose adjustment

Midazolam MDZ AUC decreased 13% No dose adjustment

Cyclosporine No effect on CsA No dose adjustment

Tacrolimus No effect on TACNo dose adjustment

Oral

Contraceptive

No effect on EE; Norgestrel

AUC increased 12%

No dose adjustment

Eley T et al. 2013. 8th IWCPHepTHer Abs O-14; Eley T et al. 2013. 8th IWCPHepTHer Abs O-15; Bifano M et al, CROI 2014; Abs 502; Bifano M

et al 2011; 62nd AASLD; ABS 1340.

DAAs in Development

Drug CYP Activity Transporters Interaction Potential

Ledipasvir Little metabolism

Not Inhibitor of CYP

or UGT

Not Inducer of CYP

or UGT

Transported by P-gp

(likely)

Inhibits intestinal

P-gp (weak)

Inhibits OATP1B1/3

(weak)

Weak

Asunaprevir Metabolised by

CYP3A4

Induces CYP3A4

(weak)

Inhibits CYP2D6

(weak)

Transported by P-gp,

OATP1B1/3

Inhibits P-gp (weak),

OATP1B1/3

Moderate

Eley T et al, 2013, 8th Int Workshop on Clin Pharm of Hep Ther; Abs O-13; Eley T et al, 2011, 62nd AASLD Abs 381; Eley T et al

2012, 7th Int Workshop on Clin Pharm of Hep Ther; Abs O-4; Kirby B et al 2013, 8th Int Workshop on Clin Pharm of Hep Ther;

Abs O-20; Mathias A, 14th Int Workshop on Clin Pharm of HIV Ther, Session 5

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

Transported by

P-gp

Moderate

ABT-333 Metabolised by

CYP2C8 > CYP3A4 >

CYP2D6

Inhibits UGT1A1

Transported by

P-gp

Inhibits OATP1B1

Moderate

Abbvie – Personal Communication

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.

Thank you

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

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; 14th Int Workshop on Clin Pharm of HIV Ther, Session 5; Sane R et al 2011, 46th EASL, Abs 1236; Sabo JP et al,

52nd ICAAC, Abs A-1248; Bertz R 2013; 14th Int Workshop on Clin Pharm of HIV Ther, Session 5; Bifano M et al, 2013, 8th Int

Workshop on Clin Pharm of Hep Ther, Abs O-15; Amblard F et al; Bioorg Med Chem Lett 23; 2031-2034.

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