Slide 1

Current Drugs: Drug-Drug Interactions

David Back University of Liverpool UK

David Back University of Liverpool

May 2013

HCV med

Co-med

Reduced Efficacy

Toxicity

The major effect of DAAs is to increase concentrations of co-meds but they may also decrease AND co-meds can interact with DAA

Clinical Pharmacology of DAAs DRUG CYP450 Non-

CYP450 Transport Proteins

Telaprevir CYP3A4 • Substrate • Inhibitor

• Transported by P-gp

• Inhibits P-gp • Inhibits

OATP1B1

Boceprevir CYP3A4 • Substrate • Inhibitor

AKR substrate

• Transported by P-gp

• Inhibits P-gp • Inhibits

OATP1B1; OCT1/2

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.

Clinical case: patient characteristics at time of treatment

BMI: body mass index; Hb: haemoglobin; HCV: hepatitis C virus; HDL: high-density lipoprotein

54-year-old male Smoker and no alcohol abuse Treatment naïve

Description

Genotype: HCV G1a Fibrosis stage: F3

HCV disease characteristics

BMI: 28 Type 2 diabetes (taking metformin) High cholesterol and cardiovascular risk >20% (taking atorvastatin) – Total

Chol: 1.70 g/L; HDL: 0.42 g/L Hypertension (taking propranolol) Suffering from mild depression (receiving behavioural therapy) Hb level: 14 g/dL

Other medical information

DDIs: patient’s medications

Telaprevir

Atorvastatin

PR

Metformin

Propranolol

Which medications are a concern with telaprevir?

ED: erectile dysfunction http://www.hep-druginteractions.org

Renal excretion – no interaction expected but we are constantly learning about renal transporters

Not anticipated to cause a problem when combined with DAAs

Metabolised by CYP2D6 (major) – no interaction expected

Metformin

Propranolol

Telaprevir increases exposure to statins

AUC: area under curve 1. Telaprevir EU SmPC

2. http://www.hep-druginteractions.org

Other recommendations:1,2

Telaprevir Recommendation

Atorvastatin AUC ↑788% Contra-indicated

Simvastatin Contra-indicated (CYP 3A4 substrate) Pravastatin Rosuvastatin

Potential interaction may require close monitoring or change of dosing

Treatment decision

Because of interactions Atorvastatin was temporarily stopped for

12 weeks after consultation with the cardiologist No changes were made to the

metformin and propranolol prescriptions

Week 2–8 visits: results

Patient health Patient develops an upper

respiratory tract infection (deemed unrelated to treatment) He develops mild rash His depression worsens

(becomes moderate)

Telaprevir + PR

HCV RNA levels

0

2

4

6

0 4 8 12

HCV

RNA

(log 1

0 IU

/mL)

Weeks

Management of the patient’s upper respiratory tract infection

Clarithromycin

CYP 3A inhibitor & substrate Concern about increase in

telaprevir exposure Also concern of increase in

CLA – this may warrant ECG monitoring due to the possible risk of QT prolongation

A 5-day course of azithromycin was chosen due its reduced likelihood of interactions

Azithromycin

Not a CYP 3A inhibitor or substrate Drug interactions unlikely

http://www.hep-druginteractions.org ECG: electrocardiogram

Choose carefully

Management of mild rash: which corticosteroid?

• Not recommended with telaprevir and boceprevir • Prednisone and methylprednisolone are CYP3A substrates;

levels may significantly increase and lead to side effects

Systemic cortico-steroids

• OK to use concomitantly with HCV PIs • Although not expected to cause significant systemic

absorption – be watchful (lessons form HIV)

Topically applied steroids

http://www.hep-druginteractions.org; Cacoub P, et al. J Hepatol 2012;56:455–463

In this patient, a topically applied corticosteroid (betamethasone) was initiated

Interaction is unlikely*

Venlafaxine

Paroxetine Fluoxetine

Antidepressants and telaprevir

Interaction is likely, caution is advised

Sertraline

Trazodone Mirtazapine

http://www.hep-druginteractions.org

Some Antidepressants are metabolized by CYP 3A4

Some Antidepressants metabolized primarily by non CYP 3A4

* Caution – note escitalopram

Week 8: patient has a car accident

The patient has a car accident at week 8 (breaking his leg) The emergency unit requests advice since the patient informed them about his Hep C medication? The internist wants to administer Morphine and iv Midazolam

Interaction with morphine and midazolam

http://www.hep-druginteractions.org; Telaprevir EU SmPC

Based on metabolism and clearance, a clinically significant interaction is unlikely. Morphine

Midazolam IV

Midazolam IV exposure is likely to be increased (respiratory depression and/or prolonged sedation risk)

Co-administration should be done in a setting ensuring clinical monitoring and appropriate medical management

Back home, the patient is prescribed paracetamol

0

2

4

6

0 12 24 36

HC

V R

NA

(log 1

0 IU

/mL)

Weeks

Treatment outcome: summary

Telaprevir + PR PR

SVR12

Rash disappeared; topical steroid stopped

Depression symptoms improved

Morphine and midazolam IV

Betamethasone Fluoxetine Restart statin

HCV med

HIVmed

Reduced Efficacy

Toxicity

In a co-infected patient we now need to manage the interactions between the HCV and HIV medication as well as other co-meds

Co- med

ATV/r DRV/r LPV/r Efavirenz Rilpivirine Etravirine Raltegravir Elvitegravir/cobi Maraviroc NRTIs

Telaprevir Boceprevir Ribavirin Drugs in pipeline

HCV – HIV DDIs: The predictable and the

unpredictable!

Drug TVR effect on AUC (exposure) BOC effect on

AUC (exposure) Cyclosporine A

4.6-fold increase 2.7-fold increase

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

Telaprevir & Boceprevir increase exposure to CYP3A substrates: Perpetrator

Vourvahis M et al. IWCPHT 2013 Abs O-17

Effect of Boceprevir and Telaprevir on the PK of Maraviroc – CYP3A4 drug

Slide 20

Conclusions

Maraviroc should be dosed at 150 mg BID when co-administered with either TVR or BOC – consistent with recommendations for potent CYP3A inhibitors. No dose modification for TVR or BOC

(relative to historical data).

Effect of Telaprevir and Boceprevir on the PK of Rilpivirine (CYP3A4)

The effect of the DAA on Rilpivirine PK was < 12% Finding consistent with CYP3A inhibition

Increase in RPV exposure probably not clinically significant

and no dose adjustment recommended.

Rhee EG, et al. CROI 2013; Atlanta, GA. #537; Kakuda T et al; IWCPHT, 2012, Barcelona, #O-18

Parameter TVR on Rilpivirine BOC on Rilpivirine

Cmin, ng/mL ↑ 93% ↑ 51%

Cmax, ng/mL ↑ 49% ↑ 15%

AUC, ng.hr/mL ↑ 78% ↑ 39%

Effect of Boceprevir on Dolutegravir PK DOL metabolised: UGT1A1 (major) & CYP3A4 (minor)

Slide 23

Effect of Telaprevir on Dolutegravir PK

Similar to Raltegravir – AUC is increased by 30%

Interactions of Telaprevir with Boosted HIV PIs (Healthy volunteer data)

Co-administered drug n

LSM ratio (90% CI), based on AUC

HIV PI Telaprevir Lopinavir/r

(LPV/r) 21 1.06 0.46

Atazanavir/r (ATV/r) 20 1.17* 0.8

Darunavir/r (DRV/r) 20 0.6 0.65

Fosamprenavir/r (fAPV/r) 20 0.53 0.68

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

Telaprevir EU SmPC

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)

But remember that ritonavir has inhibited ~95% of CYP3A

activity so TVR and BOC are exerting other effects.

Effect of Ritonavir and Cobicistat (GS-9350) on midazolam (CYP3A4 drug) clearance

RTV and Cobi are potent inhibitors of CYP3A4

What if the interaction between Telaprevir & Boceprevir and

Boosted HIV PIs was similar to the Methadone interaction?

But what if the HCV PI and HIV PI interaction was similar to TVR-Methadone?:

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

Med

ian

unbo

und

R-

met

hado

ne C

min

(ng/

mL)

Methadone Methadone + TVR

10

60

110

160

210

10.63 10.45

Methadone Methadone + TVR

5

7

9

11

13

15 M

edia

n fr

ee fr

actio

n

of R

-met

hado

ne (%

)

Methadone Methadone + TVR

5

7

9

11

13

9.98

7.92

260

146

91

Tota

l Cm

in o

f R-

met

hado

ne (n

g/m

L)

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

Protein Binding Displacement

Effect of Protein Binding on Darunavir PK with and without Telaprevir

Bertelsen K. IWCPHT 2013.

Bertelsen K IWCPHT 2013

Effect of Protein Binding on Telaprevir PK with and without Darunavir/r

Bertelsen K. IWCPHT 2013

What if DDI’s were ‘significantly’ different in HCV patients

compared to healthy volunteers?

Slide 34

Parameter HCV-infected

Albumin ↓*1

α1-acid glycoprotein ↑↓3

Gastric pH ↑4

Cytokines ↑6

CYP450’s expression or function ↓5

Transporter expression or function ?

* Magnitude of effect dependent on stage of liver involvement † Also hemodynamic changes (portal systemic shunting) and renal changes with hepatic impairment

1 Nagao Y & Sata M. Virology Journal 2010; 7: 375; 2 Monga HK et al. Clin Infect Dis 2001;

33: 240-7; 3 Ozeki T et al. Br J Exp Path 1988; 69: 589-95; 4 Nam YJ et al. Korean J Hepatol 2004; 10: 216-22; 5 Frye RF et al. Clinical Pharmacol Ther 2006; 80: 235-45;

6Huang et al Clin Pharmacol Ther 2010; 87: 32-36

Most DDI studies are in Healthy Subjects: Physiological Changes in Patients

Slide 35

Frye RF et al. Clinical Pharmacol Ther 2006; 80: 235-45

Maybe this would lead you to think that a CYP3A drug would automatically be increased in hepatic impairment!

CYP3A4

0

20

40

60

80

100

CP-A (6) CP-B (21) CP-C (21)*

% o

f con

trol

Johnson TN et al. Clinical Pharmacokin 2010; 49: 189-206

CYP enzyme expression with progressive hepatic impairment

CYP3A4

Slide 36 Impact of Hepatic Impairment on

Telaprevir PK

• Reduced Absorption • Increased clearance

due to reduced protein binding

Impact of Hepatic Impairment on Boceprevir PK

Treitel M et al., Clin Pharmacokin 2012; 51: 619-628.

Slide 40

Suggests

• Complex interplay between an individual drug and hepatic function.

• Involves CYP3A4 and probably transporters • Involves protein binding (TVR 59-76%; BOC

75%; Daclatasvir 99%; Asunaprevir 99%) • Clear differences in hepatic impairment on PK

of the DAAs

Need DDI data in target population – healthy volunteers can only be a guide

HIV-HCV Interaction Studies

The HIV-HCV interaction studies to date have mostly been performed in Healthy volunteers: some are unexpected and difficult to explain.

Need information on PK in HCV patients – the magnitude of interactions maybe different – due to difference in enzyme or transporter expression.

Mechanisms such as protein binding displacement may be involved. Need data.

Interferon may be exerting enough anti HIV activity to protect against ‘low’ HIV drug concentration.

What about DDI’s and the next generation of DAA’s?

Management of Hep Drug-Drug Interactions

45

Dianummer 1Dianummer 2Dianummer 3Clinical case:�patient characteristics at time of treatmentDDIs: patient’s medicationsWhich medications are a concern with telaprevir?Telaprevir increases exposure to statinsTreatment decisionWeek 2–8 visits: resultsManagement of the patient’s upper�respiratory tract infectionManagement of mild rash: which corticosteroid?Antidepressants and telaprevirWeek 8: patient has a car accidentInteraction with morphine and midazolam Treatment outcome: summaryDianummer 16HCV – HIV DDIs:� The predictable and the unpredictable!�Dianummer 18Dianummer 19ConclusionsEffect of Telaprevir and Boceprevir on the PK of Rilpivirine (CYP3A4)Dianummer 22Dianummer 23Interactions of Telaprevir with Boosted HIV PIs�(Healthy volunteer data)�Interaction of Boceprevir and Boosted HIV PIs�(Healthy volunteer data)But remember that ritonavir has inhibited ~95% of CYP3A activity so TVR and BOC are exerting other effects.�Dianummer 27What if the interaction between Telaprevir & Boceprevir and Boosted HIV PIs was similar to the Methadone interaction?�But what if the HCV PI and HIV PI interaction was similar to TVR-Methadone?: Dianummer 30Dianummer 31Dianummer 32What if DDI’s were ‘significantly’ different in HCV patients compared to healthy volunteers?�Dianummer 34Dianummer 35Dianummer 36Dianummer 37Dianummer 38Dianummer 39SuggestsHIV-HCV Interaction StudiesWhat about DDI’s and the� next generation of DAA’s?�Management of Hep Drug-Drug InteractionsDianummer 44Dianummer 45