THIRD JOINT CONFERENCE
OF BHIVA AND BASHH 2014
Professor David Back
University of Liverpool
1-4 April 2014, Arena and Convention Centre Liverpool
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
Date
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.
April 2014
1-4 April 2014, Arena and Convention Centre Liverpool
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
1
Brief Introduction: David Back
2
Efficacy and Tolerability of DAAs in coinfected patients: Massimo Puoti
3
Case-based Discussion: Fiona Marra;
Massimo Puoti
4
Conclusions
OTC: over the counter
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.
‘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?
DAAs: Approved or………
Drug
Telaprevir
Metabolism
 Metabolised by
CYP3A4
 Inhibits CYP3A4
 Metabolised by
Boceprevir CYP3A4; AKR
 Inhibits CYP3A4
Transporters
 Transported by P-gp
 Inhibits P-gp; OATP1B1/2
High
 Transported by P-gp;
BCRP
 Inhibits P-gp; OCT1/2
High
 Metabolised by
 Tranported by P-gp
 Mild inhibitor of intestinal
Simeprevir CYP3A4
 Inhibits intestinal (not
P-gp
hepatic) CYP3A4
 Inhibits OATP1B1, MRP2
 Metabolised by
Sofosbuvir cathepsin A; CES1.
 Not metabolised by or
inhibits CYPs
Interaction
Risk
 Transported by P-gp and
BCRP
 Inhibition (weak) of
intestinal P-gp; BCRP
Moderate
Low
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.
DAAs: Approved or………
Drug
Telaprevir
Metabolism
 Metabolised by
CYP3A4
 Inhibits CYP3A4
 Metabolised by
Boceprevir CYP3A4; AKR
 Inhibits CYP3A4
Transporters
 Transported by P-gp
 Inhibits P-gp; OATP1B1/2
High
 Transported by P-gp;
BCRP
 Inhibits P-gp; OCT1/2
High
 Metabolised by
 Tranported by P-gp
 Mild inhibitor of intestinal
Simeprevir CYP3A4
 Inhibits intestinal (not
P-gp
hepatic) CYP3A4
 Inhibits OATP1B1, MRP2
 Metabolised by
Sofosbuvir cathepsin A; CES1.
 Not metabolised by or
inhibits CYPs
Interaction
Risk
 Transported by P-gp and
BCRP
 Inhibition (weak) of
intestinal P-gp; BCRP
Moderate
Low
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
Perpetrator
ARV or
co-med
DAA
Victim
Antiretrovirals and Interaction Potential
High Risk
Medium Risk
Lower/Low Risk
Boosted PIs
Rilpivirine
Dolutegravir
Perpetrators – enzyme
and transporter
Inhibition
Victim of enzyme
inhibition and induction.
Also absorption.
Victim of enzyme
induction and absorption
interactions.
EVG/cobi
Maraviroc
Raltegravir
Perpetrators – enzyme
and transporter
inhibition
Victim of enzyme
inhibition and induction.
Victim of few induction
and absorption
interactions
Efavirenz,
nevirapine,
etravirine
Perpetrators – enzyme
and transporter
induction
Most NRTIs
Slide 15
Perpetrator
DAA or
co-med
ARV
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 UGT1A1
Probable inhibition of OATP1B1, MRP2
(Perpetrator)
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
Interaction of Faldaprevir (FDV) and ARVs
Effect of ARV
on FDV AUC
Victim
Effect of FDV
on ARV AUC
Perpetrator
Darunavir/r
2.29-fold
increase
15% increase
(Healthy) but
50% decrease
(HIV-HCV)
Atazanavir/r
2.19-fold
increase
No effect
(HIV-HCV)
RTV Inhibits CYP3A4
Use FDV at 120 mg/day
35% decrease
16% increase
(Healthy)
EFV induces CYP3A4
Use FDV at 240 mg/day
No effect
2.7-fold increase
(Healthy)
FDV likely inhibits P-gp
22% decrease
22% increase
(Healthy)
Intestinal/renal transport
No dose adjustment
Drug
Efavirenz
Raltegravir
Tenofovir
Mechanism/
Recommendation
RTV Inhibits CYP3A4
Use FDV at 120 mg/day
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
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
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
DCV AUC decreased 18%
No dose adjustment
Atazanavir/r
Omeprazole
Bifano M et al 2013; 18: 931-941; Bifano M et al; 2013;EASL Abs 794.;
Effect of Daclatasvir on Co-meds:
Perpetrator
Drug
Effect of Daclatasvir on
co-med
Sofosbuvir
SOF 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 TAC
Oral
Contraceptive
No effect on EE; Norgestrel
AUC increased 12%
Recommendation
No dose adjustment
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
Ledipasvir
CYP Activity
Transporters
 Little metabolism
 Transported by P-gp
 Not Inhibitor of CYP
(likely)
or UGT
 Inhibits intestinal
 Not Inducer of CYP
P-gp (weak)
or UGT
 Inhibits OATP1B1/3
(weak)
Asunaprevir  Metabolised by
CYP3A4
 Induces CYP3A4
(weak)
 Inhibits CYP2D6
(weak)
 Transported by P-gp,
OATP1B1/3
 Inhibits P-gp (weak),
OATP1B1/3
Interaction
Potential
 Weak
 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
MK-5172




MK-8742
 Metabolised by CYP3A4  Transported by
 Does not Inhibit CYP3A4
P-gp
 Inhibits UGT1A1 (weak)  Transported by
OATP1B1 (?)
Metabolised by CYP3A4
Inhibits (weak) CYP3A4
Inhibits CYP2C8
Inhibits UGT1A1 (weak)
 Transported by
P-gp & OATP1B1
 Inhibits BCRP?
Interaction
Potential
 Moderate
 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
Faldaprevir  Metabolised by
CYP3A4
 Inhibits CYP3A4 (240
mg dose)
 Inhibits CYP2C9 (240
mg dose)
 Inhibits UGT1A1
Daclatasvir  Metabolised by
CYP3A4
 Does not inhibit major
CYPs
Transporters
Interaction
Potential
 Transported by
 Moderate
P-gp, MRP2,
OATP1B1
 Probable inhibitor of
OATP1B1/3; MRP2
 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 2DAA combination of ABT-450/r + ABT-333

〆鷲贔

First-Line Raltegravir (RAL) + Darunavir/Ritonavir (DRV/r) is

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