Treatment of HCV Coinfection : Navigating the Interactions

IAS–USAFrom JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

Treatment of HCV Coinfection:Navigating the Interactions

Jennifer J. Kiser, PharmDAssistant Professor

Department of Pharmaceutical SciencesUniversity of Colorado School of Pharmacy

From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

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DDI: Basic PrinciplesBOC and TVR Pharmacology

Identifying Interactions withConcomitant Medications

Identifying Interactions with Antiretroviral Agents

Bermuda Triangle

Managing the Interactions

SVR

HCV Treatment:A Journey


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CYP450 and Drug Metabolism

CYP1A2 CYP2E1

CYP3A4

CYP2C

CYP2D6

*Flockhart DA, Tanus-Santos JE. Arch Intern Med 2002;162:405-412.

Majority of marketed medications are metabolized by (or substrates for) CYP3A4*

Drugs that inhibit CYP3A raise concentrations of CYP3A substrates

Drugs that induce CYP3A lower concentrations of CYP3A substrates

Slide 3 of 39


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CYP450 Inhibition

Inhibiting drug added

Time

DrugConcentration

Slide 4 of 39

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CYP450 Induction

Time

DrugConcentration

Inducing drug added

Slide 5 of 39

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BOC and TVR are CYP3A substrates• BOC and TVR PK affected by CYP3A inhibitor

(ketoconazole) and inducer (efavirenz)• Data presented as geometric mean ratios (GMR), i.e.,

ratio of concentrations A+B vs. A alone

• AKR inhibitors, diflunisal1 and ibuprofen4, do not increase BOC exposures

BOC GMR TVR GMRCmax AUC Cmin Cmax AUC Cmin

Ketoconazolea 1.411 2.311 NR 1.242 1.622 NREfavirenzb 0.921 0.811 0.561 0.913 0.743 0.533

a BOC: ketoconazole 400mg BID x 6 days, BOC single 400mg dose TVR: ketoconazole single 400mg dose, TVR single 750mg doseb BOC: EFV 600mg QD x 16 days, BOC 800mg TID x 6 days TVR: EFV 600mg QD x 20 days, TVR 750mg Q8H x 10 days

1Kassserra C, et al. CROI 2011, Abstract 118, 2Garg V, et al. 6th IWCP Hepatitis Therapy, 2011, abstract PK-13, 3van Heeswijk R, 18th CROI 2011, abstract 119, 4boceprevir prescribing information


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BOC and TVR are CYP3A Inhibitors

• TVR a more potent CYP3A inhibitor

Midazolam GMR Atorvastatin GMRAUC Cmax AUC Cmax

BOC AUC12 = 5.31 2.81 2.33 2.73

TVR AUC24 = 9.02 2.92 7.94 10.64

1BOC: midazolam single 4mg oral dose, BOC 800mg TID x 6 days2TVR: midazolam single 2mg oral dose, TVR 750mg Q8H x 11 days,340mg single dose420mg daily

1Kassserra C, et al. CROI 2011, Boston, MA, Abstract 118, 2Garg V, J Clin Pharm 2012 Jan 26 [Epub ahead of print], 3Hulskotte EGJ, et al. HepDART 2011,4Lee JE, et al. AAC 2011;55(1):4569-74


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Drug TransportersSystemic Circulation

Sinusoidal Membrane

Bile

NTCP

OAT2

Systemic Circulation

OCT1P-gp

MRP2MRP3

MRP4

BCRP ABCG5/G8

BSEP

MDR3

Canalicular Membrane

OATP1B1

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Concept of a Therapeutic Index

Intensity of overall exposure to an antiviral drug

0

20

40

60

80

100

Pro

babi

lity

of E

ffect

(%) Viral Inhibition

Toxicities

Therapeutic Index

Pharmacokinetic Variability – Food, Genetics, Degree of Liver Damage, Body Weight


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Patient Case• 57 yo African American female being considered for triple

therapy for HCV– HIV

• Diagnosed 2005, sexually acquired, CD4 nadir~200• HIV RNA = target not detected, CD4=1000 (40%) (Feb 2013)

– Hepatitis C 1a• Treatment naïve• Biopsy (June 2012)

– grade 2 inflammation, stage 2 fibrosis• HCV RNA = 3,270,000 (Aug 2012)

– GERD– Hypertension– Chronic Pain– Schizoaffective Disorder– Personality DisorderFrom JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

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Patient Case

• HIV– Raltegravir 400mg BID– Tenofovir DF 300mg QD– Emtricitabine 150mg QD

• GERD– Omeprazole 20mg QD

• Chronic Pain– Oxycodone 5-10mg Q6H prn

• Psychotropics– Sertraline 50mg QD– Quetiapine 300mg QHS

• Hypertension– Amlodipine 5mg QD


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Antihypertensives• ACE inhibitors and diuretics ok• Metabolized to some extent by CYP3A, so

consider dose reductions– Beta blockers: carvedilol and nebivolol – ARBs: irbesartan and losartan

• Calcium channel blockers– Amlodipine Cmax and AUC increased 1.27-

and 2.79-fold by TVR, so a reduced dose should be considered

Kiser JJ, et al. Hepatology 2012;55(5):1620


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Antidepressant Exposures Likely Reduced by BOC and TVR

1Hulskotte EGJ, et al. HepDART 2011 3Best BM, et al. 14th CROI 2007, abstract 5744Sekar V, et al. 8th International Congress on Drug Therapy in HIV Infection 2006, abstract P295

Escitalopram AUC ↓21% by BOC (t1/2 ↓ from 31 to 22 hrs)1

With HIV protease inhibitors, paroxetine and sertraline exposures are reduced.3,4


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Antipsychotics

• Quetiapine ↑ 335% with potent CYP3A inhibitor ketoconazole

• Cases of toxicity with HIV PIs

• Avoid quetiapine• Dosage of aripiprazole

and iloperidone should be halved

Kiser JJ, et al. Hepatology 2012;55(5):1620

Grimm SW, et al. Br J Clin Pharmacol 2006;61:58


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Opioids• Primarily metabolized by CYP3A, so may

require dose reduction:– Oxycodone– Tramadol– Fentanyl

• Hydrocodone, codeine, morphine, hydromorphone, oxymorphone okay

Kiser JJ, et al. Nature Reviews Gastro & Hepatol [Accepted]


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Interaction Potential of Concomitant Medications with BOC and TVR

Avoid or Use With Caution (Requires Investigation) SafeOral Contraceptives Psychotropics Gastric Acid ModifiersPhosphodiesterase

InhibitorsHerbal Supplements Opioid Replacements

HMG-CoA Reductase Inhibitors

Pain Medications

Antiretroviral Drugs CardiovascularImmunosuppressants Corticosteroids

Anxiolytics AntimycobacterialsAnticonvulsants AntifungalsErgot Derivatives Alpha-1 adrenoreceptor

antagonist

Kiser JJ, et al. Hepatology 2012;55(5):1620, Kiser JJ, et al. Nature Reviews Gastro & Hepatol [Accepted]


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Mean HIV PI PK Profiles

0 2 4 6 8 10 12 0 2 4 6 8 10 12

LPV/r ATV/r

DRV/r fAPV/r

AUC

AUC 47%AUC 40%

AUC 17%

n=19

n=11

n=20n=16

n=12 n=7

n=11n=18

Time (hours)

0

4000

8000

12000

LPV

conc

entr

ation

(ng/

mL)

0 2 4 6 8 10 12

ATV

conc

entr

ation

(ng/

mL)

0 6 12 18 24Time (hours)

4000

3000

2000

1000

0

Time (hours)

DRV

conc

entr

ation

(ng/

mL)

6000

4000

2000

0

APV

conc

entr

ation

(ng/

mL)

Time (hours)

4000

3000

2000

1000

0

PI alonePI + TVR

APV = amprenavir

PI alonePI + TVR

PI alonePI + TVR

PI alonePI + TVR

Van Heeswijk R, et al. CROI 2011, Boston, MA, abstract 119

Cmin ↔ Cmin ↑ 85%

Cmin ↓ 56%Cmin ↓ 42%

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Mean TVR PK Profiles

AUC = area under the curve

AUC 54%

AUC 20%

AUC 32%AUC 35%

TVR alone

TVR + ARV

n=14 n=17 n=16 n=20

n=12 n=14 n=11 n=18

Time (hours)

0

1000

2000

3000

TVR

conc

entr

ation

(ng/

mL)

LPV ATV DRV fAPV

0 2 4 6 8 0 2 4 6 8

0 2 4 6 8 0 2 4 6 8

Van Heeswijk R, et al. CROI 2011, Boston, MA, abstract 119

Cmin ↓ 52% Cmin ↓ 15% Cmin ↓ 32% Cmin ↓ 30%

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BOC and RTV-boosted PI DDI Study

Coadministration with BOC also decreased the AUC of ritonavir in all three groups with ritonavir AUC decreasing 34%, 22%, and 27% in the ATV, LPV, and DRV cohorts respectively.

Hulskotte EGJ. CROI, March 5-8, 2012, Seattle, WA, abstract 771LB

BOC PK AUC Cmax Cmin

w/ ATV/r ↓5% ↓7% ↓12%w/ LPV/r ↓45% ↓50% ↓57%w/ DRV/r ↓32% ↓25% ↓35%

ATV AUC ↓ 35%, Cmin ↓ 49% LPV AUC ↓ 34%, Cmin ↓ 43%

DRV AUC ↓ 44%, Cmin ↓ 59%


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Summary of Interactions with BOC and TVR and RTV-boosted HIV PI

BOC TVRHIV PI BOC HIV PI TVR

ATV/r ↓ ↔ ↑ ↓DRV/r ↓ ↓ ↓ ↓fAPV/r No data No data ↓ ↓LPV/r ↓ ↓ ↔ ↓

• Inconsistent• Unexpected• Difficult to Explain• Possibly Multifactorial


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Possible Mechanisms for Interactions with HIV/HCV Protease Inhibitors

1. Enzyme Induction?

2. Decrease in Bioavailability?

3. Altered Protein Binding?


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NNRTI Interactions with BOC and TVR

BOC TVRNNRTI BOC NNRTI TVR

RPV ↑39%1 ↔1 ↑79%2 ↔2

ETV ↓29%3 ↔3 ↔2 ↓25%2

1Rhee E, et al. 20th CROI, 2013 Atlanta, GA2Kakuda TN, et al. 7th Int Workshop on Clin Pharm HIV Therapy, 2012 Barcelona, Spain3Hammond KP, Kiser JJ, JAIDS 2013;62(1):67


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BOC and TVR okay with RAL

TVR1:• RAL and RAL-glucuronide AUC

increased 31% and 37%, respectively by TVR

• Similar changes in RAL-glucuronide suggest no effect of TVR on UGT1A1

• ↑ RAL likely due to P-gp inhibition by TVR

1Van Heeswijk R, et al. 51st ICAAC, Chicago, IL, Sept 17-20, 2011, abstract 1738a2de Kanter CTMM, et al. 19th CROI, Seattle, WA, March 5-8, 2012, abstract 772LB

BOC2:• RAL AUC ↔


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Maraviroc Interaction with BOC and TVR vs. HIV PI

Vourvahis M, et al. Int Workshop on Clin Pharm HIV Therapy, Amsterdam, Netherlands, 2013

Co-administered drug (dose) N

Ratio (90% CI) of maraviroc PK parameters with/without co administered drug ‑

(no effect=1.00)

AUCtau Cmax Cmin

Saquinavir/r (1000/100 mg BID) 11 9.77 (7.87, 12.14) 4.78 (3.41, 6.71) 11.3 (8.96, 14.1)

Telaprevir (750 mg TID) 14 9.49 (7.94, 11.34) 7.81 (5.92, 10.32) 10.17 (8.73, 11.85)

Ketoconazole (400 mg QD) 12 5.00 (3.98, 6.29) 3.38 (2.38, 4.78) 3.75 (3.01, 4.69)

Atazanavir/r (300/100 mg QD) 12 4.88 (4.40, 5.41) 2.67 (2.32, 3.08) 6.67 (5.78, 7.70)

Darunavir/r (600/100 mg BID) 12 4.05 (2.94, 5.59) 2.29 (1.46, 3.59) 8.00 (6.35, 10.1)

Lopinavir/r (400/100 mg BID) 11 3.95 (3.43, 4.56) 1.97 (1.66, 2.34) 9.24 (7.98, 10.7)

Atazanavir (400 mg QD) 12 3.57 (3.30, 3.87) 2.09 (1.72, 2.55) 4.19 (3.65, 4.80)

Boceprevir (800 mg TID) 14 3.02 (2.53, 3.59) 3.33 (2.54, 4.36) 2.78 (2.40, 3.23)

Ritonavir (100 mg BID) 8 2.61 (1.92, 3.56) 1.28 (0.79, 2.09) 4.55 (3.37, 6.13)

Fosamprenavir/r(700/100 mg BID) 14 2.49 (2.19, 2.82) 1.52 (1.27, 1.82) 4.74 (4.03, 5.57)

Grea

test

to le

ast e

ffect

on

MVC

AU

C

AUCtau, area under the plasma concentration-time curve over the dosage interval; Cmin, minimum plasma concentration; DDI, drug-drug interaction; Cmax, maximum plasma concentration; QD, once daily


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HCV PI:ARV Interaction ScorecardBoceprevir Telaprevir

ATV/r BOC ↔; ATV ↓ TVR ↓; ATV ↑DRV/r BOC ↓; DRV ↓ TVR ↓; DRV ↓fAPV/r No data TVR ↓; APV ↓LPV/r BOC ↓; LPV ↓ TVR ↓; LPV ↔NFV No data No dataEFV BOC ↓; EFV ↔ TVR ↓*; EFV ↔RPV BOC ↔; RPV ↑ TVR ↔; RPV ↑ETV BOC ↔; ETV ↓ TVR ↓; ETV ↔RAL BOC ↔; RAL ↔ TVR ↔; RAL ↑ELV/cobi No data No dataMVC BOC ↔; MVC ↑** TVR ↔; MVC ↑**

*TVR dose 1125mg Q8H, **Use MVC 150mg BIDFrom JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

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Resources for Drug Interactions• Not specific to ARV

– University of Liverpool• www.hep-druginteractions.org

– Toronto General Hospital• http://www.hcvdruginfo.ca/

– University of Buffalo ACTG Pharmacology Support Laboratory

• http://tdm.pharm.buffalo.edu/home/di_search/

• Specific to ARV– DHHS Guidelines Drug Interaction Tables

• www.aidsinfo.nih.gov


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

http://www.hcvdruginfo.ca/

http://www.hcvdruginfo.ca/

http://tdm.pharm.buffalo.edu/home/di_search/

http://tdm.pharm.buffalo.edu/home/di_search/

http://www.aidsinfo.nih.gov/

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Pharmacology and Interaction Potential of Phase 3 Agents

CYP3A substrate?

Interaction Potential ARV DDI data

Faldaprevir (PI)

√ Moderate ᴓ CYP3A, weak ᴓ CYP2C9,1 ᴓ

UGT1A12

DRV/r ↑FDV 130%EFV ↓ FDV 35%TDF ↓ FDV 22%3

Simeprevir (PI)

√ Mild ᴓ CYP1A2 and intestinal 3A4,4

ᴓ OATP1B1 and MRP25

EFV ↓ SPV 71%,DRV/r ↑ SPV 360%,

↔TDF, RPV, and RAL6

Daclatasvir (NS5A)

√ Substrate and ᴓ of P-gp ATV/r ↑ DCVEFV ↓ DCV

TDF ↔ DCV7

Sofosbuvir (NI)

X Transporters? Intracellular

phosphorylation?

DRV/r, RAL, RPV, TDF/FTC/EFV + SOF and uridine plasma

metabolite largely unchanged8

1Sabo JP, 52nd ICAAC 2012, 2Sane R, 46th EASL 2011, 3Sabo JP, CROI 2013, 4Sekar V, 45th EASL 2010 , 5Huisman MT, 61st AASLD 2010, 6Ouwerkerk-Mahadevan S, IDSA 2012, 7Bifano M, 19th CROI 2012, 8Kirby B, AASLD 2012


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Conclusion• BOC and TVR have complex pharmacology• Interactions are not easily predicted• Identification and management of

interactions is critical with these agents• Next “batch” of Hepatitis C agents less

likely to act as perpetrators in interactions but still victims


Treatment of HCV Coinfection : Navigating the Interactions

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