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Treatment of HCV Coinfection : Navigating the Interactions

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

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  1. 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.

  2. 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.

  3. Slide 3 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

  4. Inhibiting drug added Slide 4 of 39 CYP450 Inhibition Drug Concentration Time

  5. Inducing drug added Slide 5 of 39 CYP450 Induction Drug Concentration Time

  6. 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.

  7. 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.

  8. 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

  9. Concept of a Therapeutic Index From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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

  18. 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)

  19. 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.

  20. 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.

  21. 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.

  22. 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.

  23. 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.

  24. 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.

  25. 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.

  26. 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.

  27. 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.

  28. 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.

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