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IAS–USA From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. Treatment of HCV Coinfection: Navigating the Interactions Jennifer J. Kiser, PharmD Assistant.

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Presentation on theme: "IAS–USA From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. Treatment of HCV Coinfection: Navigating the Interactions Jennifer J. Kiser, PharmD Assistant."— Presentation transcript:

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

2 Slide 2 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. DDI: Basic Principles BOC and TVR Pharmacology Identifying Interactions with Concomitant Medications Identifying Interactions with Antiretroviral Agents Bermuda Triangle Managing the Interactions SVR HCV Treatment: A Journey 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. Slide 3 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

4 Slide 4 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. CYP450 Inhibition Inhibiting drug added Time Drug Concentration Slide 4 of 39

5 Slide 5 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. CYP450 Induction Time Drug Concentration Inducing drug added Slide 5 of 39

6 Slide 6 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. 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, diflunisal 1 and ibuprofen 4, do not increase BOC exposures BOC GMRTVR GMR CmaxAUCCminCmaxAUCCmin Ketoconazole a NR NR Efavirenz b 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 1 Kassserra C, et al. CROI 2011, Abstract 118, 2 Garg V, et al. 6th IWCP Hepatitis Therapy, 2011, abstract PK-13, 3 van Heeswijk R, 18th CROI 2011, abstract 119, 4 boceprevir prescribing information From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

7 Slide 7 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. BOC and TVR are CYP3A Inhibitors TVR a more potent CYP3A inhibitor Midazolam GMRAtorvastatin GMR AUCCmaxAUCCmax BOCAUC 12 = TVRAUC 24 = BOC: midazolam single 4mg oral dose, BOC 800mg TID x 6 days 2 TVR: midazolam single 2mg oral dose, TVR 750mg Q8H x 11 days, 3 40mg single dose 4 20mg daily 1 Kassserra C, et al. CROI 2011, Boston, MA, Abstract 118, 2 Garg V, J Clin Pharm 2012 Jan 26 [Epub ahead of print], 3 Hulskotte EGJ, et al. HepDART 2011, 4 Lee JE, et al. AAC 2011;55(1): From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

8 Slide 8 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. Drug Transporters Systemic Circulation Sinusoidal Membrane Bile NTCP OAT2 Systemic Circulation OCT1 P-gp MRP2 MRP3 MRP4 BCRP ABCG5/G8 BSEP MDR3 Canalicular Membrane OATP1B1 Slide 8 of 39

9 Slide 9 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. Concept of a Therapeutic Index From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

10 Slide 10 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. Approach to Identifying and Managing Drug Interactions in HCV Treatment Kiser JJ, et al. Nature Reviews Gastro & Hepatol [Accepted] From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

11 Slide 11 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. 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.

12 Slide 12 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. 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.

13 Slide 13 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. 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 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.

14 Slide 14 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. Antidepressant Exposures Likely Reduced by BOC and TVR 1 Hulskotte EGJ, et al. HepDART Best BM, et al. 14th CROI 2007, abstract Sekar V, et al. 8th International Congress on Drug Therapy in HIV Infection 2006, abstract P295 Escitalopram AUC ↓21% by BOC (t 1/2 ↓ from 31 to 22 hrs) 1 With HIV protease inhibitors, paroxetine and sertraline exposures are reduced. 3,4 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

15 Slide 15 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. 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 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

16 Slide 16 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. 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.

17 Slide 17 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. Interaction Potential of Concomitant Medications with BOC and TVR Avoid or Use With Caution (Requires Investigation)Safe Oral ContraceptivesPsychotropicsGastric Acid Modifiers Phosphodiesterase Inhibitors Herbal SupplementsOpioid Replacements HMG-CoA Reductase Inhibitors Pain Medications Antiretroviral DrugsCardiovascular ImmunosuppressantsCorticosteroids AnxiolyticsAntimycobacterials AnticonvulsantsAntifungals Ergot DerivativesAlpha-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.

18 Slide 18 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. Mean HIV PI PK Profiles LPV/rATV/r DRV/r fAPV/r AUC  AUC  47%AUC  40% AUC  17% n=19 n=11 n=20 n=16 n=12 n=7 n=11 n=18 Time (hours) LPV concentration (ng/mL) ATV concentration (ng/mL) Time (hours) Time (hours) DRV concentration (ng/mL) APV concentration (ng/mL) Time (hours) PI alone PI + TVR APV = amprenavir PI alone PI + TVR PI alone PI + TVR PI alone PI + TVR Van Heeswijk R, et al. CROI 2011, Boston, MA, abstract 119 Cmin ↔Cmin ↑ 85% Cmin ↓ 56% Cmin ↓ 42% Slide 18 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

19 Slide 19 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. 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=16n=20 n=12 n=14n=11n=18 Time (hours) TVR concentration (ng/mL) LPVATVDRVfAPV Van Heeswijk R, et al. CROI 2011, Boston, MA, abstract 119 Cmin ↓ 52% Cmin ↓ 15%Cmin ↓ 32% Cmin ↓ 30% Slide 19 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

20 Slide 20 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. 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 AUCC max C min 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% From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

21 Slide 21 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. Summary of Interactions with BOC and TVR and RTV-boosted HIV PI BOCTVR HIV PIBOCHIV PITVR ATV/r↓↔↑↓ DRV/r↓↓↓↓ fAPV/rNo data ↓↓ LPV/r↓↓↔↓ Inconsistent Unexpected Difficult to Explain Possibly Multifactorial From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

22 Slide 22 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. 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.

23 Slide 23 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. NNRTI Interactions with BOC and TVR BOCTVR NNRTIBOCNNRTITVR RPV↑39% 1 ↔1↔1 ↑79% 2 ↔2↔2 ETV↓29% 3 ↔3↔3 ↔2↔2 ↓25% 2 1 Rhee E, et al. 20 th CROI, 2013 Atlanta, GA 2 Kakuda TN, et al. 7 th Int Workshop on Clin Pharm HIV Therapy, 2012 Barcelona, Spain 3 Hammond KP, Kiser JJ, JAIDS 2013;62(1):67 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

24 Slide 24 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. BOC and TVR okay with RAL TVR 1 : 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 Van Heeswijk R, et al. 51 st ICAAC, Chicago, IL, Sept 17-20, 2011, abstract 1738a 2 de Kanter CTMM, et al. 19 th CROI, Seattle, WA, March 5-8, 2012, abstract 772LB BOC 2 : RAL AUC ↔ From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

25 Slide 25 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. 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) AUC tau C max C min Saquinavir/r (1000/100 mg BID) (7.87, 12.14)4.78 (3.41, 6.71)11.3 (8.96, 14.1) Telaprevir (750 mg TID) (7.94, 11.34)7.81 (5.92, 10.32)10.17 (8.73, 11.85) Ketoconazole (400 mg QD) (3.98, 6.29)3.38 (2.38, 4.78)3.75 (3.01, 4.69) Atazanavir/r (300/100 mg QD) (4.40, 5.41)2.67 (2.32, 3.08)6.67 (5.78, 7.70) Darunavir/r (600/100 mg BID) (2.94, 5.59)2.29 (1.46, 3.59)8.00 (6.35, 10.1) Lopinavir/r (400/100 mg BID) (3.43, 4.56)1.97 (1.66, 2.34)9.24 (7.98, 10.7) Atazanavir (400 mg QD) (3.30, 3.87)2.09 (1.72, 2.55)4.19 (3.65, 4.80) Boceprevir (800 mg TID) (2.53, 3.59)3.33 (2.54, 4.36)2.78 (2.40, 3.23) Ritonavir (100 mg BID)82.61 (1.92, 3.56)1.28 (0.79, 2.09)4.55 (3.37, 6.13) Fosamprenavir/r (700/100 mg BID) (2.19, 2.82)1.52 (1.27, 1.82)4.74 (4.03, 5.57) Greatest to least effect on MVC AUC AUC tau, area under the plasma concentration-time curve over the dosage interval; C min, minimum plasma concentration; DDI, drug-drug interaction; C max, maximum plasma concentration; QD, once daily From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

26 Slide 26 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. HCV PI:ARV Interaction Scorecard BoceprevirTelaprevir ATV/rBOC ↔; ATV ↓TVR ↓; ATV ↑ DRV/rBOC ↓; DRV ↓TVR ↓; DRV ↓ fAPV/rNo dataTVR ↓; APV ↓ LPV/rBOC ↓; LPV ↓TVR ↓; LPV ↔ NFVNo data EFVBOC ↓; EFV ↔TVR ↓*; EFV ↔ RPVBOC ↔; RPV ↑TVR ↔; RPV ↑ ETVBOC ↔; ETV ↓TVR ↓; ETV ↔ RALBOC ↔; RAL ↔TVR ↔; RAL ↑ ELV/cobiNo data MVCBOC ↔; MVC ↑**TVR ↔; MVC ↑** *TVR dose 1125mg Q8H, **Use MVC 150mg BID From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

27 Slide 27 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. Resources for Drug Interactions Not specific to ARV – University of Liverpool – Toronto General Hospital – University of Buffalo ACTG Pharmacology Support Laboratory Specific to ARV – DHHS Guidelines Drug Interaction Tables From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

28 Slide 28 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. Pharmacology and Interaction Potential of Phase 3 Agents CYP3A substrate? Interaction PotentialARV DDI data Faldaprevir (PI) √Moderate ᴓ CYP3A, weak ᴓ CYP2C9, 1 ᴓ UGT1A1 2 DRV/r ↑FDV 130% EFV ↓ FDV 35% TDF ↓ FDV 22% 3 Simeprevir (PI) √Mild ᴓ CYP1A2 and intestinal 3A4, 4 ᴓ OATP1B1 and MRP2 5 EFV ↓ SPV 71%, DRV/r ↑ SPV 360%, ↔TDF, RPV, and RAL 6 Daclatasvir (NS5A) √Substrate and ᴓ of P-gpATV/r ↑ DCV EFV ↓ DCV TDF ↔ DCV 7 Sofosbuvir (NI) XTransporters? Intracellular phosphorylation? DRV/r, RAL, RPV, TDF/FTC/EFV + SOF and uridine plasma metabolite largely unchanged 8 1 Sabo JP, 52 nd ICAAC 2012, 2 Sane R, 46th EASL 2011, 3 Sabo JP, CROI 2013, 4 Sekar V, 45 th EASL 2010, 5 Huisman MT, 61 st AASLD 2010, 6 Ouwerkerk-Mahadevan S, IDSA 2012, 7 Bifano M, 19th CROI 2012, 8 Kirby B, AASLD 2012 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

29 Slide 29 of 39 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. 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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