Treatment of HCV Coinfection:
Navigating the Interactions
Jennifer J. Kiser, PharmD
Assistant Professor
Department of Pharmaceutical Sciences
University of Colorado School of Pharmacy
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
IAS–USA
Slide 2 of 39
HCV Treatment:
A Journey
DDI: Basic Principles
BOC and TVR Pharmacology
Managing the Interactions
Bermuda
Triangle
Identifying Interactions with
Concomitant Medications
Identifying Interactions with
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. Antiretroviral Agents
SVR
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CYP450 and Drug Metabolism
CYP1A2
Majority of marketed
medications
are metabolized by (or
substrates for) CYP3A4*
CYP2E1
Drugs that inhibit CYP3A raise
concentrations of CYP3A
substrates
CYP2C
Drugs that induce CYP3A lower
concentrations of CYP3A
substrates
CYP2D6
CYP3A4
*Flockhart DA, Tanus-Santos JE. Arch Intern Med 2002;162:405-412.
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 4 of 39
CYP450 Inhibition
Drug
Concentration
Inhibiting drug added
Time
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 5 of 39
CYP450 Induction
Drug
Concentration
Inducing drug added
Time
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 6 of 39
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
BOC GMR
Cmax
AUC
Cmin Cmax
AUC
Cmin
1.242
1.622
NR
0.921 0.811 0.561 0.913
0.743
0.533
Ketoconazolea 1.411 2.311
Efavirenzb
TVR GMR
NR
a BOC:
ketoconazole 400mg BID x 6 days, BOC single 400mg dose
TVR: ketoconazole single 400mg dose, TVR single 750mg dose
b 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
• AKR inhibitors, diflunisal1 and ibuprofen4, do not
increase BOC exposures
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
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 7 of 39
BOC and TVR are CYP3A Inhibitors
Midazolam GMR
Atorvastatin GMR
AUC
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 days
midazolam single 2mg oral dose, TVR 750mg Q8H x 11 days,
340mg single dose
420mg daily
2TVR:
• TVR a more potent CYP3A inhibitor
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
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 8 of 39
Drug Transporters
Systemic Circulation
Systemic Circulation
NTCP
OAT2
ABCG5/G8
BCRP
OATP1B1
MRP2
OCT1
Sinusoidal Membrane
Bile
BSEP
MRP4
MDR3
P-gp
Canalicular Membrane
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
MRP3
Slide 9 of 39
Concept of a Therapeutic Index
100
Probability of Effect (%)
Viral Inhibition
80
Therapeutic Index
60
Toxicities
40
20
0
Pharmacokinetic Variability – Food, Genetics, Degree of Liver Damage, Body Weight
Intensity of overall exposure to an antiviral drug
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 11 of 39
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 Disorder
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 12 of 39
Patient Case
• HIV
• Psychotropics
– Raltegravir 400mg BID
– Sertraline 50mg QD
– Tenofovir DF 300mg QD
– Quetiapine 300mg QHS
– Emtricitabine 150mg QD • Hypertension
• GERD
– Amlodipine 5mg QD
– Omeprazole 20mg QD
• Chronic Pain
– Oxycodone 5-10mg Q6H prn
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 13 of 39
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 1.27and 2.79-fold by TVR, so a reduced dose
should be considered
Kiser JJ, et al. Hepatology 2012;55(5):1620
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 14 of 39
Antidepressant Exposures Likely
Reduced by BOC and TVR
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
1Hulskotte
EGJ, et al. HepDART 2011
3Best BM, et al. 14th CROI 2007, abstract 574
4Sekar V, et al. 8th International Congress on Drug Therapy in HIV Infection 2006, abstract P295
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 15 of 39
Antipsychotics
• Quetiapine ↑ 335%
with potent CYP3A
inhibitor ketoconazole
• Cases of toxicity with
HIV PIs
• Avoid quetiapine
• Dosage of aripiprazole
and iloperidone should
be halved
Grimm SW, et al. Br J Clin Pharmacol 2006;61:58
Kiser JJ, et al. Hepatology 2012;55(5):1620
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 16 of 39
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]
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 17 of 39
Interaction Potential of Concomitant
Medications with BOC and TVR
Avoid or Use With Caution (Requires Investigation)
Safe
Oral Contraceptives
Psychotropics
Gastric Acid Modifiers
Phosphodiesterase
Inhibitors
Herbal Supplements
Opioid Replacements
HMG-CoA Reductase
Inhibitors
Pain Medications
Antiretroviral Drugs
Cardiovascular
Immunosuppressants
Corticosteroids
Anxiolytics
Antimycobacterials
Anticonvulsants
Antifungals
Ergot Derivatives
Alpha-1 adrenoreceptor
antagonist
Kiser JJ, et al. Hepatology 2012;55(5):1620, Kiser JJ, et al. Nature Reviews Gastro & Hepatol [Accepted]
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 18 of 39
Van Heeswijk R, et al. CROI 2011, Boston, MA, abstract 119
Mean HIV PI PK Profiles
4000
LPV/r
n=19
8000
n=12
4000
PI alone
PI + TVR
Cmin ↔
ATV concentration (ng/mL)
LPV concentration (ng/mL)
12000
PI alone
PI + TVR
3000
2000
n=7
1000
AUC 
n=11
Cmin ↑ 85% AUC 17%
0
0
0
2
4
6
8
Time (hours)
10
12
0
6
12
18
Time (hours)
DRV/r
PI alone
PI + TVR
4000
n=16
2000
Cmin ↓ 42%
n=11
AUC 40%
24
fAPV/r
APV concentration (ng/mL)
6000
DRV concentration (ng/mL)
ATV/r
PI alone
PI + TVR
4000
3000
n=20
2000
1000
n=18
Cmin ↓ 56% AUC 47%
0
0
0
2
4
6
8
Time (hours)
10
12
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
0
2
4
6
8
Time (hours)
10
12
APV = amprenavir
Van Heeswijk R, et al. CROI 2011, Boston, MA, abstract 119
Slide 19 of 39
Mean TVR PK Profiles
0 2 4 6 8
ATV
LPV
TVR concentration (ng/mL)
n=14
0 2 4 6 8
fAPV
DRV
n=17
n=16
n=20
3000
TVR alone
2000
TVR + ARV
1000
n=12
0
n=14
n=11
n=18
Cmin ↓ 52%
Cmin ↓ 15%
Cmin ↓ 32%
Cmin ↓ 30%
AUC 54%
AUC 20%
AUC 35%
AUC 32%
0 2 4 6 8
0 2 4 6 8
From JJ Kiser, MD, at Chicago, IL: May 20,Time
2013, (hours)
IAS-USA.
AUC = area under the curve
Slide 20 of 39
BOC and RTV-boosted PI DDI Study
ATV AUC ↓ 35%, Cmin ↓ 49%
DRV AUC ↓ 44%, Cmin ↓ 59%
LPV AUC ↓ 34%, Cmin ↓ 43%
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.
w/ ATV/r
w/ LPV/r
w/ DRV/r
Hulskotte EGJ. CROI, March 5-8, 2012, Seattle, WA, abstract 771LB
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
AUC
↓5%
↓45%
↓32%
BOC PK
Cmax
Cmin
↓7% ↓12%
↓50% ↓57%
↓25% ↓35%
Slide 21 of 39
Summary of Interactions with BOC and
TVR and RTV-boosted HIV PI
BOC
TVR
HIV PI
BOC
HIV PI
TVR
ATV/r
↓
↔
↑
↓
DRV/r
↓
↓
↓
↓
fAPV/r
No data
No data
↓
↓
LPV/r
↓
↓
↔
↓
•
•
•
•
Inconsistent
Unexpected
Difficult to Explain
Possibly Multifactorial
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 22 of 39
Possible Mechanisms for Interactions
with HIV/HCV Protease Inhibitors
1. Enzyme Induction?
2. Decrease in Bioavailability?
3. Altered Protein Binding?
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 23 of 39
NNRTI Interactions with BOC and TVR
RPV
ETV
BOC
NNRTI
BOC
↑39%1
↔1
↓29%3
↔3
1Rhee
TVR
NNRTI
TVR
↑79%2
↔2
↔2
↓25%2
E, et al. 20th CROI, 2013 Atlanta, GA
2Kakuda TN, et al. 7th Int Workshop on Clin Pharm HIV Therapy, 2012 Barcelona, Spain
3Hammond KP, Kiser JJ, JAIDS 2013;62(1):67
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 24 of 39
BOC and TVR okay with RAL
BOC2:
• RAL AUC ↔
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
1
st
Van Heeswijk R, et al. 51 ICAAC, Chicago, IL, Sept 17-20, 2011, abstract 1738a
2de Kanter CTMM, et al. 19th CROI, Seattle, WA, March 5-8, 2012, abstract 772LB
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 25 of 39
Greatest to least effect on MVC AUC
Maraviroc Interaction with BOC and
TVR vs. HIV PI
Co-administered drug
(dose)
N
Ratio (90% CI) of maraviroc PK parameters
with/without co-administered drug
(no effect=1.00)
AUCtau
Saquinavir/r (1000/100 mg BID) 11 9.77 (7.87, 12.14)
Cmax
Cmin
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)
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
Vourvahis M, et al. Int Workshop on Clin Pharm HIV Therapy, Amsterdam, Netherlands, 2013
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 26 of 39
HCV PI:ARV Interaction Scorecard
ATV/r
DRV/r
Boceprevir
BOC ↔; ATV ↓
BOC ↓; DRV ↓
Telaprevir
TVR ↓; ATV ↑
TVR ↓; DRV ↓
fAPV/r
LPV/r
NFV
EFV
No data
BOC ↓; LPV ↓
No data
BOC ↓; EFV ↔
TVR ↓; APV ↓
TVR ↓; LPV ↔
No data
TVR ↓*; EFV ↔
RPV
ETV
RAL
BOC ↔; RPV ↑
BOC ↔; ETV ↓
BOC ↔; RAL ↔
TVR ↔; RPV ↑
TVR ↓; ETV ↔
TVR ↔; RAL ↑
No data
No data
BOC ↔; MVC ↑**
TVR ↔; MVC ↑**
ELV/cobi
MVC
*TVR dose 1125mg Q8H, **Use MVC 150mg BID
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 27 of 39
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
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Pharmacology and Interaction
Potential of Phase 3 Agents
Slide 28 of 39
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 ↑ DCV
EFV ↓ 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
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 29 of 39
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
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.