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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. . HCV Treatment: A Journey.

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treatment of hcv coinfection navigating the interactions
Treatment of HCV Coinfection:Navigating the Interactions

Jennifer J. Kiser, PharmDAssistant ProfessorDepartment of Pharmaceutical SciencesUniversity of Colorado School of Pharmacy

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

slide2

HCV Treatment:

A Journey

DDI: Basic Principles

BOC and TVR Pharmacology

Managing the Interactions

Bermuda Triangle

SVR

Identifying Interactions with

Concomitant Medications

Identifying Interactions with

Antiretroviral Agents

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

slide3

Slide 3 of 39

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

cyp450 inhibition

Inhibiting drug added

Slide 4 of 39

CYP450 Inhibition

Drug

Concentration

Time

cyp450 induction

Inducing drug added

Slide 5 of 39

CYP450 Induction

Drug

Concentration

Time

boc and tvr are cyp3a substrates
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

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

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.

boc and tvr are cyp3a inhibitors
BOC and TVR are CYP3A Inhibitors
  • TVR a more potent CYP3A inhibitor

1BOC: midazolam single 4mg oral dose, BOC 800mg TID x 6 days

2TVR: midazolam single 2mg oral dose, TVR 750mg Q8H x 11 days,

340mg single dose

420mg 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. HepDART2011,4Lee JE, et al. AAC 2011;55(1):4569-74

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

drug transporters

Slide 8 of 39

Drug Transporters

Systemic Circulation

Systemic Circulation

NTCP

OATP1B1

ABCG5/G8

BCRP

Bile

MRP3

BSEP

MRP2

OAT2

MRP4

OCT1

MDR3

P-gp

Canalicular Membrane

Sinusoidal Membrane

concept of a therapeutic index
Concept of a Therapeutic Index

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

patient case
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.

patient case1
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

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

antihypertensives
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

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

antidepressant exposures likely reduced by boc and tvr
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.

antipsychotics
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 ClinPharmacol 2006;61:58

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

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

opioids
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.

interaction potential of concomitant medications with boc and tvr
Interaction Potential of Concomitant Medications with BOC and TVR

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.

mean hiv pi pk profiles
Mean HIV PI PK Profiles

4000

3000

2000

1000

0

Slide 18 of 39

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

LPV/r

ATV/r

12000

PI alone

PI + TVR

n=19

8000

ATV concentration (ng/mL)

LPV concentration (ng/mL)

n=12

n=7

4000

PI alone

PI + TVR

n=11

Cmin ↔

Cmin ↑ 85%

AUC 

AUC 17%

0

0 2 4 6 8 10 12

0 6 12 18 24

Time (hours)

Time (hours)

DRV/r

fAPV/r

6000

4000

2000

0

PI alone

PI + TVR

PI alone

PI + TVR

4000

3000

2000

1000

0

n=20

n=16

APV concentration (ng/mL)

DRV concentration (ng/mL)

Cmin ↓ 42%

n=11

n=18

Cmin ↓ 56%

AUC 40%

AUC 47%

0 2 4 6 8 10 12

0 2 4 6 8 10 12

Time (hours)

Time (hours)

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

APV = amprenavir

mean tvr pk profiles
Mean TVR PK Profiles

0

0

2

2

4

4

6

6

8

8

0

2

4

6

8

Slide 19 of 39

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

LPV

ATV

DRV

fAPV

n=17

n=16

n=20

n=14

3000

TVR alone

2000

TVR concentration (ng/mL)

TVR + ARV

1000

n=14

n=11

n=18

n=12

Cmin ↓ 52%

Cmin ↓ 30%

Cmin ↓ 15%

Cmin ↓ 32%

AUC54%

AUC 32%

AUC 20%

AUC 35%

0

0

2

4

6

8

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

AUC = area under the curve

Time (hours)

boc and rtv boosted pi ddi study
BOC and RTV-boosted PI DDI Study

ATV AUC ↓ 35%, Cmin ↓ 49%

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.

DRV AUC ↓ 44%, Cmin ↓ 59%

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

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

summary of interactions with boc and tvr and rtv boosted hiv pi
Summary of Interactions with BOC and TVR and RTV-boosted HIV PI
  • Inconsistent
  • Unexpected
  • Difficult to Explain
  • Possibly Multifactorial

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

possible mechanisms for interactions with hiv hcv protease inhibitors
Possible Mechanisms for Interactions with HIV/HCV Protease Inhibitors
  • Enzyme Induction?
  • Decrease in Bioavailability?
  • Altered Protein Binding?

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

nnrti interactions with boc and tvr
NNRTI Interactions with BOC and TVR

1Rhee E, et al. 20th CROI, 2013 Atlanta, GA

2Kakuda TN, et al. 7thInt 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.

boc and tvr okay with ral
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

1Van Heeswijk R, et al. 51st 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.

maraviroc interaction with boc and tvr vs hiv pi
Maraviroc Interaction with BOC and TVR vs. HIV PI

Greatest to least effect on MVC AUC

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.

hcv pi arv interaction scorecard
HCV PI:ARV Interaction Scorecard

*TVR dose 1125mg Q8H, **Use MVC 150mg BID

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

resources for drug interactions
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
Pharmacology and Interaction Potential of Phase 3 Agents

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.

conclusion
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.