Slide 1

Interaction profile of the new DAAs

David Back

University of Liverpool

UK

David Back

University of Liverpool

June 8th 2012

Why worry about Drug – Drug Interactions

(DDIs) in managing HCV patients?

Current interactions (limited) involving pegylated

interferon/ribavirin are well documented.

However the DAAs have increased potential for DDIs

An Interaction can alter the exposure of either the DAA or

a co-medication

– Concern is i) loss of antiviral efficacy or toxicity and ii)

loss of efficacy or toxicity of co-medication.

DDI: drug–drug interaction; HCV: hepatitis C virus

Enzyme inhibition and induction: effect of introducing

another drug when steady state has already been reached

1 2 3 4 5 6 7 8 9 10 11 12

Dru

g C

on

c.

Days

Inhibiting Drug

Enzyme Inhibition Enzyme Induction

Dru

g C

on

c.

Days

1 2 3 4 5 6 7 8 9 10 11 12

Inducing Drug

Understanding the disposition of the

currently licensed DAAs

Drug Dosing

regimen

CYP

metabolism

Non-CYP

metabolism

P-gp

Transporter

Telaprevir

Q8h

Taken with food

(20 g of fat)

CYP 3A4:

Metabolised

by

Markedly

Inhibits

– Substrate

Inhibitor

Boceprevir 3 x daily

Taken with food

CYP 3A4:

Metabolised

by

Markedly

Inhibits

AKR

Metabolise

d by

Substrate

Telaprevir EU SmPC; Boceprevir EU SmPC

Kassera C, et al. CROI 2011. Abstract 118; Garg V, et al. CROI 2011. Abstract 629

AKR: aldo-keto reductase; DAA: direct-acting antiviral

Q8h: every 8 hours; RTV: ritonavir; tid: three times daily

Telaprevir and Boceprevir are metabolised

by and inhibit CYP3A4

CYP 3A isozymes involved in the

metabolism of majority of drugs CYP 3A isozymes are the

most abundant in the liver

Proportion of total CYP enzymes

present in human liver

Proportion of drugs that are

substrates for major CYP enzymes

CYP 1A2

CYP 2A6 CYP 2B6

CYP 2C8

CYP 2C9

CYP 2C19

CYP 2D6

CYP 2E1

CYP 3A

CYP 1A2

CYP 2A6

CYP 2B6 CYP 2C8

CYP 2C9 CYP 2C19

CYP 2D6

CYP 2E1 CYP 3A

Hacker MP, et al. Pharmacology: Principles and Practice. Academic Press 2009

CYP: cytochrome P450

All percentages are approximate. For illustrative purposes,

hepatic CYP enzymes present at <5% are all represented as 3.3%

Drugs can be metabolised in the

Gastrointestinal tract and Liver

Small Intestines Liver

Adapted from Bailey DG, et al. Br J Clin Pharmacol. 1998:46:101–10 P-gp: P-glycoprotein

CYP3A

Pgp

CYP3A

Telaprevir & Boceprevir increase exposure

to CYP3A substrates: Perpetrator

Drug TVR effect on the

AUC (exposure)

BOC effect on the

AUC (exposure)

Cyclosporine A

4.6-fold increase 2.7-fold increase

Tacrolimus

70-fold increase 17-fold increase

Midazolam 3.4-fold increase (i.v)

9-fold increase (oral) 6.3-fold increase (oral)

Atorvastatin 7.9-fold increase 2.3-fold increase

Garg V, et al. Heptatology 2011:54:20–27; Garg V, et al. J Clin Pharmacol 2012 ; Lee JE, et al. Antimicrob Agents Chemother 2011;55:4569–74;

Telaprevir EU SmPC; Hulskotte EGJ et al HEPDart 2011; Abs 122 and Abs 123; Kessara C et al, CROI 2011, Abs 118; Boceprevir EU SmPC

Manageable

Difficult to manage

CI CI

CI Dose reduce

Telaprevir & Boceprevir decrease exposure

to other CYP-metabolised drugs:

Perpetrator

Co-medication

TVR effect BOC effect

AUC AUC

Escitalopram (SSRI)

Metabolised by CYP2C19 35%

21%

van Heeswijk R, et al. IWCPHT 2010. Abstract 12; Telaprevir EU SmPC; Hulskotte EGJ et al HEP Dart 2011; Abs 121; Boceprevir EU SmPC.

Mechanism: Not clearly determined

Doses may need to be increased when combined with telaprevir; but

dose adjustment not anticipated with boceprevir.

Telaprevir & Boceprevir decrease exposure

to other CYP-metabolised drugs:

Perpetrator

Garg V, et al. IWCPHT 2011. Abstract PK_17Telaprevir EU SmPC;

Oral Contraceptive Effect of TVR on OC AUC

Ethinyl estradiol ↓ 28%

Norethindrone ↓ 11%

Additional methods of non-hormonal contraception should be used; ie

hormonal contraceptives may be continued but may not be reliable during

and immediately following TVR dosing

Oral Contraceptive Effect of BOC on OC AUC

Ethinyl estradiol ↓ 24%

Drospirenone 99%

Kassera C et al CROI 2011; Abs 118; Boceprevir EU SmPC.

Enzyme inducing agents reduce telaprevir

and boceprevir exposure: Victim

Telaprevir EU SmPC; van Heeswijk R et al, CROI 2011; Abstract 119.

Co-medication

Effect on telaprevir Effect on boceprevir

AUC AUC

Efavirenz (600 mg qd) 26% 19% (Cmin 44%)

Decrease in Telaprevir exposure substantially offset by increasing

dose to 1125 mg q8h.

The clinical outcome of the observed reduction of boceprevir

concentrations has not been directly assessed

Modified from Kassera C, et al. CROI 2011. Abstract 118 Boceprevir EU SmPC

Telaprevir interaction with Methadone:

a further complication:

During telaprevir co-administration vs methadone alone:

– Total Cmin of R-methadone reduced by 31%

– Free fraction of R-methadone increased by 26%

– No change in the unbound (effective) concentration of R-methadone

Me

dia

n u

nb

ou

nd

R-

me

tha

do

ne

Cm

in (

ng

/mL

)

Methadone Methadone

+ TVR

10

60

110

160

210

10.63 10.45

Methadone Methadone

+ TVR

5

7

9

11

13

15

Me

dia

n f

ree

fra

cti

on

of

R-m

eth

ad

on

e (

%)

Methadone Methadone

+ TVR

5

7

9

11

13

9.98

7.92

260

146

91

To

tal C

min

of

R-

me

tha

do

ne

(n

g/m

L)

van Heeswijk R, et al. J Hepatol 2011;54(Suppl. 1):S491

Protein Binding Displacement

Telaprevir interaction with Buprenorphine

13 HCV negative subjects stable on

buprenorphine/naloxone therapy

TVR had only relatively minor effect on BUP

exposure (Cmax decreased by 20%) or nor-BUP

exposure

No subject experienced withdrawal symptoms

Luo X et al; HEP DART 2011; Abs 132

DAA Clinical Pharmacology

Targeted drug-drug interaction studies are done in

the development programme and some post-

licensing.

Telaprevir and Boceprevir are perpetrators and

victims of DDIs and this gives rise to a degree of

nervousness

Many DDIs can be explained on the basis of

interaction with CYP3A4 but not all.

DAA: direct-acting antiviral; DDI: drug-drug interaction

DAAs and Lipid Lowering Agents

Drug CYP3A4

substrate

CYP3A4

inhibitor Transporter substrate

Atorvastatin X OATP1B1/2B1

Cerivastatin X OATP1B1

Lovastatin X

Simvastatin X

Pravastatin OATP1B1/3,

Rosuvastatin OATP1B1,

Fluvastatin OATP1B1/2B1

Pitavastatin OATP1A2/1B3

Gemfibrozil 2C9

Contraindication or Caution when co-administering telaprevir and statins

with CYP3A4 mediated metabolism……but

Can you avoid using a statin during DAA treatment?

Co-administered drug Dosage

LSM ratio (90% CI), based on AUC

Co-administered drug Telaprevir

Atorvastatin 20 mg* 7.9

(6.8–9.1)

↔

15

16

DAAs and Lipid Lowering Agents

17

Contraindications with telaprevir and

boceprevir

Class Agent Telaprevir1 Boceprevir2

Alpha-1 receptor

antagonists Alfuzosin CI No recommendation

Antiarrhythmics Amiodarone, bepridil, quinidine

CI

(CI with class Ia/III

except IV lidocaine)

Bepridil contraindicated. Caution with

amiodarone/quinidine

Anticonvulsants Carbamazepine, phenobarbital, phenytoin CI No data available: not recommended

Antihistamines Astemizole, terfenadine CI No recommendation

Antimalarials Lumefantrine, halofantrine No recommendation CI

Antimycobacterials Rifampicin CI No data available: not recommended

Antipsychotics Pimozide CI CI

Benzodiazepines Oral midazolam, oral triazolam CI CI

Digestive motility

stimulants Cisapride CI No recommendation

Ergot rye derivatives Dihydroergotamine, ergonovine,

ergotamine, methylergonovine CI CI

Herbal products St. John’s wort (Hypericum perforatum) CI No recommendation

HMG-CoA reductase

inhibitors Atorvastatin, simvastatin, lovastatin CI

No data available. Therapeutic

monitoring recommended (atorvastatin,

simvastatin)

PDE5 inhibitors* Sildenafil, tadalafil CI No recommendation

Tyrosine kinase

inhibitors Not specified No recommendation CI

1. Telaprevir EU SmPC; 2. Boceprevir EU SmPC Italic: removed/not available in all countries; *for pulmonary arterial hypertension

Implications for Clinical Practice

Peg-IFN alfa + ribavirin* Peg-IFN alfa +

ribavirin Telaprevir + PR

0 48 Weeks 4 24 36 12

PR

lead-in BOC + PR

24, 32 or 44 weeks**

12 weeks

PR: peginterferon (Peg-IFN) + ribavirin

*PR must be continued up to Week 48 in patients with cirrhosis, prior partial and null responders and in

treatment-naïve patients or prior relapsers without cirrhosis not achieving undetectable HCV RNA at

Week 4 and 12 (but with HCV RNA <1000 IU/mL at these timepoints)

**In patients receiving 32 weeks of boceprevir, PR alone must be continued up to Week 48 Telaprevir EU SmPC; Boceprevir EU SmPC

HIV-HCV Co-Infection

Interaction of Telaprevir with Boosted HIV

PIs (Healthy volunteer data)

Co-administered drug n

Change in AUC (%)

HIV PI Telaprevir

Lopinavir/r

(LPV/r) 21

Atazanavir/r

(ATV/r) 20 17%* 20%

Darunavir/r

(DRV/r) 20 40% 35%

Fosamprenavir/r

(fAPV/r) 20 43% 32%

LPV/r, DRV/r and fAPV/r not recommended in combination with telaprevir

* Cmin increased by ~ 70%

Mechanistic understanding of observed DDI is inconsistent with CYP3A4

interactions

q8h: every 8 hours

Van Heeswijk R et al CROI 2011; Abs 119; Telaprevir EU SmPC

54%

Interaction of Boceprevir and Boosted HIV PIs

(Healthy volunteer data)

% Change in AUC of

Boosted PI

% Change in AUC of

Boceprevir

Atazanavir/r

Lopinavir/r

Darunavir/r

Hulskotte E et al; CROI 2012 Abs 771LB

35%

34%

44%

45%

32%

Not recommended to coadminister boceprevir and

ritonavir boosted PIs (FDA; Merck)

‘ATV/r can be considered on a case by case basis if

patient has no prior HIV drug resistance’ (EMEA)

Telaprevir & Boceprevir interaction with

NNRTIs:

NNRTI Effect of TVR on

AUC

Effect of NNRTI on

TVR AUC

Etravirine ↓ 16%

Rilpivirine 1.8-fold ↓ 8%

NNRTI Effect of BOC on

AUC

Effect of NNRTI on BOC

AUC

Etravirine ↓ 23% 10%

Rilpivirine ND ND

Based on the PK data - dose adjustment not required.

Based on the PK data - dose adjustment not considered necessary

Kakuda T et al; IWCPHT 2012; Abs 0_18; Hammond K et al, IWCPHT 2012; Abs 0-15

Telaprevir: Summary of DDIs with HIV

antiretrovirals HIV antiretroviral Recommendation

Studies completed

Atazanavir/r Clinical and laboratory monitoring for hyperbilirubinemia is

recommended

Darunavir/r

Fosamprenavir/r

Lopinavir/r Not recommended

Efavirenz TVR dose increase necessary (1125 mg q8h)

Etravirine No dose adjustment required*

Rilpivirine No dose adjustment required*

Raltegravir (non CYP) No dose adjustment required**

Tenofovir Increase in TFV (30%). Clinical and laboratory monitoring is

warranted

Telaprevir EU SmPC

All the PK Interaction studies are in HEALTHY VOLUNTEERS

* Data presented by Kakuda et al at 13th HIV Pharmacology Workshop, Barcelona, April 16-18th 2012; ** van

Heeswijk R et al; ICAAC 2011; Abs A1-1738a

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Telaprevir in Combination with Pegylated Interferon--2a+RBV in HCV/HIV-co-infected Patients: A 24-Week Treatment Interim Analysis Douglas Dieterich*1, V Soriano2, K Sherman3, P-M Girard4, J Rockstroh5, B Adiwijaya6, S McCallister6, N Adda6, L Mahnke6, M Sulkowski7, on behalf of the Study 110 Team 1Mt Sinai Sch of Med, New York, US; 2Hosp Carlos III, Madrid, Spain; 3Univ of Cincinnati , OH, US; 4Hosp St Antoine, Paris, France; 5Univ of Bonn, Germany; 6Vertex Pharm Inc, Cambridge, MA, US; 7Johns Hopkins Univ Sch Med, Baltimore, MD, US

ATV/r did not cause a decrease in TVR concentrations (cf healthy)

TVR dose increase compensated for EFV effect

ATV concentrations increased in T + P/R group by 18% in keeping

with healthy data.

Boceprevir: Summary of DDIs with HIV

antiretrovirals

HIV antiretroviral Recommendation

Studies completed

Atazanavir/r

Darunavir/r

Lopinavir/r Not recommended

Efavirenz Reduction in boceprevir levels; clinical outcome not directly

assessed

Etravirine No dose adjustment required*

Raltegravir (non CYP) No dose adjustment required**

Tenofovir No change in TFV AUC but Cmax increased by 32%. No

dose adjustment but clinical/laboratory monitoring warranted

All the PK Interaction studies are in HEALTHY VOLUNTEERS

*De Kanter C, et al. CROI 2012. Abstract 772LB; **Hammond K et al, IWCPHT 2012; Abs O-15 Abs Victrlelis SmPC

27

Boceprevir plus Peginterferon /Ribavirin for the Treatment of HCV/HIV-co-infected Patients: End of Treatment (Week-48) Interim Results J Mallolas, S Pol, A Rivero, H Fainboim, C Cooper, J Slim, S Thomson, J Wahl, W Geaves, M Sulkowski, Spain, France, Argentina, Canada, USA.

Included patients on ATV/r; LPV/r, DRV/r, Raltegravir.

EASL 2012; Abs 50

8,8 14,7

23,5 32,4 29,4 26,5

4,7

42,2

59,4

73,4 65,6 60,7

0

20

40

60

80

100

4 8 12 24 EOT SVR12

Treatment Week

P/R BOC + P/R

Pe

rce

nt

wit

h V

iro

log

ic

Re

sp

on

se

28

Boceprevir plus Peginterferon /Ribavirin for the Treatment of HCV/HIV-co-infected Patients: End of Treatment (Week-48) Interim Results J Mallolas, S Pol, A Rivero, H Fainboim, C Cooper, J Slim, S Thomson, J Wahl, W Geaves, M Sulkowski, Spain, France, Argentina, Canada, USA.

Included patients on ATV/r; LPV/r, DRV/r, Raltegravir.

3/64 pts on BOC + P/R had HIV breakthrough – not

suggestive of systematic interaction.

SVR12 by HIV Drug

PR (27%) BOC + PR (62.5%)

ATV/r 8/13 (62%) 12/18 (67%)

LPV/r 0/10 (0%) 10/15 (67%)

DRV/r 0/5 (0%) 8/12 (67%)

Other PI/r 0/3 (0%) 4/7 (57%)

Raltegravir 1/3 (33%) 3/7 (43%)

EASL 2012; Abs 50

DAA Clinical Pharmacology

The HCV-HIV interactions (Healthy volunteers) are:

unexpected, inconsistent and difficult to explain.

Need information on pharmacokinetics in HCV patients

– the magnitude of interactions maybe different.

– Interferon may be exerting enough anti HIV activity to

protect against ‘low’ HIV drug concentration.

Perhaps total concentrations reduced but ‘free’

concentrations less affected – need data!

We do have ‘safer’ ARV options until there is clarity.

What about the next generation of

DAAs?

TMC435 (Simeprivir)

Reversible NS3/4A protease

inhibitor

150 mg dose in Phase III

Weak inhibitory effect on CYP3A

suggest less DDI potential

Simmen K et al Int Liver Congress Hong Kong 2008; Abs 507. Beumont-Mauviel M et al AASLD 2011; Abs 1353 & 1354

Methadone No effect of TMC435 on either R- or S-methadone

in subjects stable on methadone therapy.

Escitalopram No effect of TMC435 on escitalopram exposure

TMC435 (Simeprivir) Interactions

Efavirenz TMC435 AUC reduced by 71%. AVOID use.

Rilpivirine No effect of RPV on TMC435 AUC. RPV exposure

increased by 12%. No Dose Adjustment.

Raltegravir TMC435 AUC decreased 11%. RPV exposure not

altered. No Dose Adjustment.

Tenofovir TMC435 AUC decreased 14%. TFV exposure

increased 18%. No Dose Adjustment.

Ouwerkerk-Mahadevan S et al 19th CROI 2012; Abs 49

And...

CYP3A

substrate?

Interaction

Potential

Interaction data

BI 201355 YES Yes Awaited

Daclatasvir YES

Yes

ATV/r increases DCV

EFV decreases DCV

TDF no effect on DCV

Alisporivir YES

Yes Awaited

Danoprevir/r YES

Boosted by

ritonavir - Yes

Awaited

GS-7977 NO Intracellular

phosphorylation

-Less

No effect on

methadone

33

Sane R et al, 46th EASL 2011; Bifano M et al; CROI 2012; Abs 618; Crabbe R et al; Exp Opin Inv Drugs 2009; 18: 211-220;

Denning JM et al AASLD 2011; Abs 372.

Thank you

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