Slide 1

Practical Management of interactions between DAA and ARVs

David Back University of Liverpool UK

David Back, Liverpool, UK

Paris: June 12th 2014

Disclosures

• Honoraria received from Gilead, Janssen, Merck, Abbvie, BMS, Boehringer-Ingelheim, Viiv.

• Research or Educational Grant support from Gilead, Janssen, Merck, Abbvie, Roche, Vertex, BMS, Boehringer-Ingelheim, Viiv.

• Presentation 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.

Molecular Virology Deciphered the viral replication cycle and identified druggable

targets.

Structural Biology Provided high-resolution structures of viral targets – allowing

modelling of drug-target interactions

Molecular & Clinical Pharmacology Shown the disposition of compounds and developed

strategies to optimise therapies – in particular in relation to drug-drug interactions.

Multiple Clinical Trials Efficacy and AEs.

Anti-HCV drugs approved and in advanced development

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

DAA Co-med

Perpetrator

Victim

Drug- Drug Interactions

Prueksaritanont T et al.

Preclinical

Studies identify drug ‘X’ as: i) Substrate of

enzyme or transporter,

ii) An inhibitor or inducer.

Healthy Volunteers

Targeted approach Predicts the nature of a DDI ie increase or decrease in exposure

Patient Population HCV

Fibrosis stage: F0, F1, F2, F3, F4. Altered expression/function of hepatic enzymes and/or transporters!

In 2011, telaprevir and boceprevir were licensed for use in HCV GT1 infection. The side effect profile of these drugs in combination with PEG IFNα and RBV are not favourable and the costs per SVR in patients with advanced hepatic fibrosis are such that they should ideally no longer be used in patients with HCV GT1 as soon as other, more efficacious, better tolerated, options are available.

Drug CYP 3A4 Transporters Non-CYP

metabolism

Telaprevir Metabolised

by Inhibits

Transported by P-gp Inhibits P-gp;

OATP1B1/2 –

Boceprevir Metabolised

by Inhibits

Transported by P-gp; BCRP

Inhibits P-gp; OCT1/2

AKR Metabolised

by

Telaprevir and Boceprevir Interactions: What have we learned?

P-gp: P-glycoprotein; AKR: aldo-keto reductase

CYP 3A isozymes are The most abundant CYP enzymes in the liver Involved in the metabolism of many drugs

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.

Importance of metabolism and transport in relation to systemic drug levels

Adapted from: Bailey DG, et al. CMAJ 2013;185:1066

Enterocytes

Hepatocytes drug

100%

1

2

CYP3A4

P-gp BCRP MRP2

OATP1A2 OATP2B1

CYP3A4

UGTs

OATP1B1 OATP1B3 OCT1

Enzyme/Transporter induction or inhibition

CYP 1A2 CYP 2A6 CYP 2B6

CYP 2C8 CYP 2C9

CYP 2C19 CYP 2D6

CYP 2E1 CYP 3A

If clearance of co-med involves just CYP3A4 – co-med levels increase.

But if other or additional metabolic pathways – co-med levels could decrease.

There may be other interaction mechanisms (eg transporter and protein binding displacement)

Telaprevir and Boceprevir Interactions: What have we learned?

ARVs cleared by CYP3A4: Maraviroc (major), Rilpivirine (major), Dolutegravir (minor) -

Predictable

Finding consistent with CYP3A inhibition Is increase in RPV exposure clinically significant? Note: No dose adjustment recommended.

De Kanter C et al CID 2013; 56: 300-306 van Heeswijk R et al; ICAAC 2011; Vourvahis M et al IWCPHT, 2013; Abs O-17

ARV exposure (AUC) Effect of TVR Effect of BOC

Maraviroc ↑ 9-fold ↑ 3-fold

Rilpivirine ↑ 78% ↑ 39%

Dolutegravir ↑ 37% ↑ 7%

Clin Pharm Review FDA Sept 2011 Eviplera SmPC 31/10/13

Why is exposure of boosted HIV PIs mainly decreased in healthy volunteer studies?

Effect of TVR & BOC on HIV Boosted PI concentrations

NOTE: RTV inhibits >90% of CYP3A activity so TVR & BOC exert other effects.

Effect of HIV Boosted on TVR & BOC concentrations

Complex enzyme – transporter interplay between the 3 components ie DAA, HIV PI, RTV; Also protein binding displacement or even absorption

effects.

Telaprevir (TVR) Boceprevir (BOC)

Atazanavir Monitor for bilirubin Consider; case-by-case

Darunavir Not recommended Not recommended

Efavirenz Increase to 1125 mg 3xday

Not recommended

Rilpivirine Recommended (but QT concerns)

Recommended

Etravirine Recommended Consider; case-by-case

Raltegravir Recommended Recommended

Dolutegravir Recommended Recommended

Known and predicted DDIs between TVR and BOC and key Anti HIV drugs

Modified from Karageorgopoulos DE et al Curr Opin Infect Dis 2014; 27: 36-45; www.hep-druginteractions.org

Are drug interactions different in HCV patients compared to healthy subjects?

Evidence that drug exposure in plasma of some DAAs is altered (note: hepatic impairment) Changes in protein binding in liver disease. Evidence that enzyme activity is altered in liver

disease Some evidence from co-infection that the

magnitude of an interaction may be different.

Effect of Mild or Moderate Hepatic Impairment on DAA PK

Drug Mild Moderate

Telaprevir AUC decreased 15% AUC decreased 46%A

Boceprevir No change AUC increased 14% (49% in severe)

Simeprevir AUC increased 2.4-fold

Sofosbuvir AUC increased 2.3-fold

Daclatasvir AUC decreased 43% AUC decreased 40%

Asunaprevir AUC decreased 21% AUC increased 9.8-fold

www.hep-druginteractions.org Data relative to normal liver function.

Are drug interactions different in HCV patients compared to healthy subjects? Evidence that drug exposure in plasma of some

DAAs is altered (note: hepatic impairment) Changes in protein binding in liver disease

Evidence that enzyme activity is altered in liver

disease Some evidence from co-infection that the

magnitude of an interaction may be different.

Daclatasvir

AUC of ARV Healthy Volunteers

HCV+ (16% cirrhotics)

ATV/r ↓ 35% ↓ 30%

DRV/r ↓ 44% ↓ 42%

EFV ↓ 20% ↓ 7%

RAL ↓ 4% ↑ 59%

15th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy.

Sofosbuvir

SOF is activated in hepatocyte Hydrolases (CES1, Cat A; HNT1)

Phosphorylated to active GS-4612003

Predominant circulating form GS-331007

SOF not metabolised by or inhibits CYP SOF interacts with P-gp (and BCRP) - Victim

Sofosbuvir and P-gp Induction

• Potent P-gp inducers in the intestine (rifampicin, St. John's wort, carbamazepine and phenytoin) may significantly decrease sofosbuvir plasma concentration leading to reduced therapeutic effect. Sofosbuvir should not be co-administered with known inducers of P-gp.

• Other P-gp inducers eg modafanil – SPC not recommended; USPI – not mentioned.

Sovaldi SPc – accessed April 12th 2014

Effect of ARVs on Sofosbuvir: Victim

Drug Effect on Sofosbuvir and GS-331007 AUC (exposure) Recommendation

Darunavir/r

SOF increased 34%; GS-331007 – no effect

No dose adjustment

Rilpivirine

No effect on SOF or GS-331007 No dose adjustment

Efavirenz No effect on SOF or GS-331007 No dose adjustment

Raltegravir No effect on SOF or GS-331007: RAL decreased 27%

No dose adjustment

Tenofovir No effect on SOF or GS-331007

No dose adjustment

Mathias A 14th Int Workshop on Clin Pharm of HIV Ther Session 5; Kirby B et al 63rd AASLD 2012; Abs 1877. ; Sofosbuvir USPI 2013

No known or anticipated interactions with antiretrovirals

Effect of Other Co-administered Drugs on Sofosbuvir: Victim

Drug Effect on Sofosbuvir and GS-331007 AUC (exposure) Recommendation

Methadone (multiple dose)

SOF increased 30%; no effect on GS-331007

No dose adjustment

Cyclosporine

SOF increased 4-fold but no effect on GS-331007 No dose adjustment

Tacrolimus No effect on SOF or GS-331007 No dose adjustment

Rifampicin Rifampicin is a potent P-gp inducer* Not recommended

Mathias A 14th Int Workshop on Clin Pharm of HIV Ther Session 5; Kirby B et al 63rd AASLD 2012; Abs 1877. ; Sofosbuvir USPI 2013

Simeprevir

Metabolised by CYP3A4 (Victim) Mild inhibitor of CYP3A4 in intestine

Inhibits OATP1B1 (Perpetrator)

Small Intestines Liver

CYP3A CYP3A UGT

Effect of ARVs on Simeprevir: Victim

Drug Effect on Simeprevir AUC (exposure)

Mechanism/ Recommendation

Darunavir/r

2.6-fold increase but SIM dose 50 mg (DRV increased 18%)

RTV Inhibits CYP3A4

Not recommended

Rilpivirine

No effect No dose adjustment

Efavirenz 70% decrease EFV induces CYP3A4 Not recommended

Raltegravir 11% decrease

No dose adjustment

Tenofovir 14% decrease (TFV increase 18%)

Intestine or renal transport No dose adjustment

Ouwerkerk-Mahadevan S et al, IDSA 2012; Abs 1618; Ouwerkerk-Mahadevan S et al, CROI 2012; Abs 49 ; Simeprevir (Olysio) USPI

Effect of ritonavir on Simeprevir PK

Ouwerkerk-Mahadevan S et al 15th Int Workshop on Clin Pharm of HIV and HEP Therapy. May 2014

Effect of ARVs on Simeprevir: Victim

Drug Effect on Simeprevir AUC (exposure)

Mechanism/ Recommendation

Darunavir/r

2.6-fold increase but SIM dose 50 mg (DRV increased 18%)

RTV Inhibits CYP3A4

Not recommended

Rilpivirine

No effect No dose adjustment

Efavirenz 70% decrease EFV induces CYP3A4 Not recommended

Raltegravir 11% decrease

No dose adjustment

Tenofovir 14% decrease (TFV increase 18%)

Intestine or renal transport No dose adjustment

Ouwerkerk-Mahadevan S et al, IDSA 2012; Abs 1618; Ouwerkerk-Mahadevan S et al, CROI 2012; Abs 49 ; Simeprevir (Olysio) USPI

Permitted Antiretrovirals with Simeprevir

1st Agent NRTIs

Raltegravir Tenofovir Maraviroc Emtricitabine Rilpivirine Lamivudine

Abacavir

www.hcvguidelines.org.

Drugs Contraindicated/Not Recommended with Simeprevir

Simeprevir Increased Simeprevir Decreased

Erythromycin Carbamazepine Clarithromycin Oxcarbamazine Telithromycin Phenobarbitone Itraconazole Phenytoin Ketoconazole Rifampicin Posaconazole Rifabutin Fluconazole Rifapentine Voriconazole Dexamethasone Milk Thistle St John’s Wort

USPI – accessed April 14th 2014

Effect of Simeprevir on Statins: Perpetrator

Drug Effect of Simeprevir on Statin AUC

Mechanism/ Recommendation

Atorvastatin

2.1-fold increase

CYP3A & OATP1B1 inhibition

Use lowest dose

Rosuvastatin

3.2-fold increase OATP1B1 inhibition Initiate with 5mg

Simvastatin 40% increase CYP3A inhibition Titrate dose carefully

Simprevir (Olysio) USPi 2013

Sofosbuvir and Simeprevir: Interaction Potential

Drug

CYP Activity

Transporters

Interaction Potential

Sofosbuvir (NS5B)

Metabolised by cathepsin A; CES1 and is phosphorylated.

Not metabolised by CYPs

No inhibition of CYP

Transported by P-gp and BCRP

Inhibition (weak) of intestinal P-gp and BCRP

Weak

Simeprevir (NS3/4A)

Metabolised by CYP3A4 Mild inhibitor of

intestinal CYP3A4 No inhibition of hepatic

CYP3A4

Tranported by P-gp Mild inhibitor of

intestinal P-gp Inhibits OATP1B1,

MRP2

Moderate

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.

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

Effect of Daclatasvir on Co-meds: Perpetrator

Drug Effect of Daclatasvir on co-med Recommendation

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 No 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.

Daclatasvir: Interaction Potential

Drug

CYP/enzyme Activity

Transporters

Interaction Potential

Daclatasvir

(NS5A) Metabolised by

CYP3A4 Does not inhibit major

CYPs

Transported by P-gp

Inhibits OATP1B1; P-gp

Moderate

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.

DAAs in Development

Drug

CYP Activity

Transporters

Interaction Potential

Ledipasvir (NS5A)

Little metabolism Not Inhibitor of CYP or

UGT Not Inducer of CYP or

UGT

Transported by P-gp Inhibits intestinal P-gp

(weak) Inhibits OATP1B1/3

(weak)

Weak

Asunaprevir (NS3/4A)

Metabolised by CYP3A4 Induces CYP3A4 and

inhibits CYP2D6 (weak)

Transported by P-gp, OATP1B1/3

Inhibits P-gp (weak), OATP1B1/3

Moderate

Faldaprevir (NS3/4A)

Metabolised by CYP3A4 Inhibits CYP3A4 (240mg) Inhibits CYP2C9 (240mg) Inhibits UGT1A1

Transported by P-gp, MRP2, OATP1B1

Probable inhibitor of OATP1B1/3; MRP2

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; 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;

Abbvie 3D (ABT-450/r; ABT-267; ABT-333)

Drug

CYP/enzyme Activity

Transporters

Interaction Potential

ABT-450 (NS3/4A)

Metabolised by CYP3A4

Inhibits CYP2C8 Inhibits UGT1A1

Transported by P-gp, OATP1B1

Inhibits OATP1B1 and OATP1B3

Moderate

ABT-267 Ombitasvir

(NS5A)

Metabolised by CYP3A4

Inhibits CYP2C8 Inhibits UGT1A1

Transported by P-gp

Moderate

ABT-333 Dasabuvir

(NS5B)

Metabolised by CYP2C8 > CYP3A4 > CYP2D6

Inhibits UGT1A1

Transported by P-gp

Inhibits OATP1B1

Moderate

Abbvie – Personal Communication

RTV has effects on multiple enzymes and transporters – Significant Interactions Formal DDI studies performed with the 3D regimen or 2D (ie ABT450/r + ABT333)

MK-5172 and MK-8742

Drug

CYP/enzyme Activity

Transporters

Interaction Potential

MK-5172 (NS3/4A)

Metabolised by CYP3A4 Inhibits (weak) CYP3A4 Inhibits CYP2C8 Inhibits UGT1A1 (weak)

Transported by P-gp & OATP1B1 Inhibits BCRP?

Moderate

MK-8742 (NS5A)

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.

HCV DDIs

A stepwise approach to DDI management

OTC: over the counter

Note all co-medications (prescribed, OTC, recreational and herbal products). Always be aware of the unexpected

1

Consult pharmacist and/or online resources 2

Amber

Are drugs necessary ?

Are there alternatives ?

Can DDI be managed ?

Change dose

Establish Monitoring

Plan

Accept risk , discuss with

patient

Stop

Switch

Yes

Yes

Yes

No

No

No

A stepwise approach to DDI management

No clinically significant interaction or interaction not anticipated. Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration. Interaction likely – do not co-administer

Ask key questions. 3

DDIs in the Evolving HCV Treatment Landscape

Polypharmacy is the new ‘norm’

Newer DAAs still have potential to cause DDIs - transporter interactions need to be clarified - use of ritonavir

Shorter treatment courses make these manageable - emphasis should be on harms, not just PK changes - special populations may have increased susceptibility

Acknowledgements Grateful thanks to: The Liverpool Website team: Saye Khoo Sara Gibbons Fiona Marra Catia Marzolini Justin Chiong www.hep-druginteractions Editorial Board