Direct acting antiviral agents (DAAs) have transformed

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1 REVIEWS A Clinician s Guide to Drug-Drug Interactions With Direct-Acting Antiviral Agents for the Treatment of Hepatitis C Viral Infection Travis B. Dick, 1 Lance S. Lindberg, 1 Debra D. Ramirez, 1 and Michael R. Charlton 2 The US Food and Drug Administration has recently approved a number of new direct-acting antiviral agents for the treatment of chronic hepatitis C virus that have significantly increased the likelihood of a virological cure. These agents are highly effective but present a substantial risk for a host of clinically relevant drug-drug interactions. These interactions must be considered both when starting and stopping any medication, including over-the-counter medications and herbal supplements. These drug-drug interactions can increase the risk of toxicity or decrease the likelihood of treatment response. Knowledge of these interactions is paramount in optimizing the success of antiviral therapy. Conclusion: In this review we summarize the available data regarding drug-drug interactions for direct-acting antiviral agents, the interactions being the most clinically relevant that are currently known; this review is intended to serve as a clinician s guide to understanding and managing these complex interactions. (HEPATOLOGY 2016;63: ) Direct acting antiviral agents (DAAs) have transformed the management of hepatitis C viral (HCV) infection. Virological cure rates of >90% are routinely achievable across HCV genotypes and irrespective of the presence of cirrhosis and prior non-daa treatment history. Although highly effective and well tolerated, DAAs present unique and important potential for drug-drug interactions that must be considered before, during, and after initiation of DAAbased therapy. This review summarizes the available data regarding the most clinically relevant drug-drug interactions for DAAs with the goal of optimizing pharmacotherapeutic outcomes. General Mechanisms of Drug-Drug Interactions Clinically relevant drug-drug interactions typically occur in either the absorption or the metabolism phase of a drug s pharmacokinetic profile. Interactions in absorption usually occur by altering intestinal ph or by directly binding the index agent. Interactions at the level of drug metabolism are also common. The cytochrome P450 (CYP450) enzyme system, particularly the 3A4 (CYP3A4) isozyme, is responsible for the oxidation of many drugs. Administering inhibitors, inducers, and/or substrates of this enzyme system can lead to clinically relevant changes in drug concentrations. 1 Similar principles of induction and inhibition apply to other enzymes that metabolize drugs. Interactions with P-glycoprotein (P-gp) and breast cancer resistance protein, active transport proteins, also have the potential to affect drug bioavailability by either increasing elimination or decreasing cellular absorption. 2,3 Both P-gp and CYP450 enzymes are found in the liver and gastrointestinal tract. 4 Orally administered medications are subject to potential elimination by intestinal CYP450 and P-gp prior to systemic absorption, a process termed first pass metabolism. Inhibiting intestinal CYP450 and P-gp with one agent can result in a second agent being more available for systemic absorption. The DAAs for the treatment of HCV are metabolized through these pathways, which makes them subject to drug-drug interactions. Figure 1 illustrates the common Abbreviations: CYP3A4, cytochrome P450 3A4; CYP450, cytochrome P450; 3D, three-dimensional; DAA, direct-acting antiviral agent; HCV, hepatitis C virus; HIV, human immunodeficiency virus; P-gp, P-glycoprotein; PPI, proton pump inhibitor. From the 1 Department of Pharmacy and the 2 Department of Transplantation, Intermountain Medical Center, Murray, UT. Received March 5, 2015; accepted May 14,

2 HEPATOLOGY, Vol. 63, No. 2, 2016 DICK ET AL. 635 Fig. 1. Metabolic pathways of potential drug-drug interactions for DAAs. The most common metabolic pathways leading to drug-drug interactions include CYP450, drug uptake transporters such as organic anion transporting polypeptide, and drug efflux transporters such as P- gp and BCRP. The figure illustrates the metabolic pathway of each DAA. When other drugs influence or are metabolized through these pathways, drug interactions can occur. Abbreviations: BCRP, breast cancer resistance protein; CYP2C8, cytochrome P450 2C8; OATP1B1/ 3, organic anion transporting polypeptides 1B1 and 1B3. sites of drug-drug interactions and the sites of metabolism for each DAA in this review. Clinically Significant Drug-Drug Interactions Human Immunodeficiency Viral Agents Protease Inhibitors. In general, protease inhibitors inhibit CYP3A isozyme activity. The potency of inhibition, however, is different among protease inhibitors for human immunodeficiency virus (HIV) and HCV. Both simeprevir and ritonavir are inhibitors of CYP3A, but ritonavir s inhibition is much more potent. When given together, the combination of simeprevir and ritonavir results in increased exposure of simeprevir by six-fold. 5 It is also possible that concurrent administration of other agents could be significantly affected by additive inhibition of both agents. Because of this increased concentration, the concomitant use of the two agents is not recommended. 5 Atazanavir, fosamprenavir, lopinavir, indinavir, nelfinavir, saquinavir, tipranavir, and ritonavir can also result in altered plasma concentrations of simeprevir. Coadministration of simeprevir with any HIV protease inhibitor is not recommended. 5 Tipranavir can decrease concentrations of both ledipasvir and sofosbuvir when given concomitantly. 6,7 Ritonavir is typically administered with tipranavir, and ritonavir also decreases concentrations of both DAAs. Coadministration of tipranavir with sofosbuvir and ledipasvir is not recommended. 7 Nonnucleoside Reverse Transcriptase Inhibitors. The combination of paritaprevir, ritonavir, ombitasvir, and dasabuvir, collectively referred to as the threedimensional (3D) regimen, is not recommended for concomitant use with rilpivirine as the concentrations of the nonnucleoside reverse transcriptase inhibitor are increased approximately two-fold and can lead to an increased risk of QTc prolongation. 8 Efavirenz is also not recommended with the 3D regimen as the combination of the 3D regimen with efavirenz resulted in liver enzyme elevations. 8 The change in concentrations of efavirenz when given with the 3D regimen has not been established. Efavirenz can also decrease the exposure of simeprevir, which may lead to a decreased therapeutic effect of simeprevir. 5 Delavirdine can increase exposure to simeprevir, while etravirine and nevirapine can decrease systemic exposure to simeprevir. The concomitant use of simeprevir with any of these agents is not recommended. 5 Efavirenz can decrease both the rate and the extent of exposure of daclatasvir. It is not yet known if this is clinically significant. 9,10 There are no published data describing the concentrations of efavirenz when given with daclatasvir. Nucleotide Reverse Transcriptase Inhibitors. Few clinically significant interactions are documented Address reprint requests to: Travis B. Dick, Pharm.D., M.B.A., B.C.P.S., Department of Pharmacy, 5121 South Cottonwood Street, Murray, UT travis.dick@imail.org; tel: ; fax: Or: Michael R. Charlton, M.D., F.R.C.P., Hepatology and Liver Transplantation, 5121 South Cottonwood Street, Murray, UT michael.charlton@imail.org; tel: ; fax: Copyright VC 2015 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI /hep Potential conflict of interest: Dr. Charlton consults and received grants from Gilead, AbbVie, Merck, and Janssen.

3 636 DICK ET AL. HEPATOLOGY, February 2016 Table 1. Effect of Select HIV Antiviral Agents on Daclatasvir, Ledipasvir, Sofosbuvir, Simeprevir, and Ribavirin Daclatasvir 9,10 Ledipasvir 7 Sofosbuvir 6 Simeprevir 5,24 C max AUC C max AUC C max AUC C max AUC Darunavir/ritonavir Expected to " but Expected to " but " 45% " 39% " 45% " 34% " 79% " 159% ND to date* ND to date* Efavirenz # 17%* # 32%* # 34% # 34% # 19% # 6% # 51%* # 71%* Raltegravir ND ND $ $ $ $ $ # 7% $ # 11% Rilpivirine ND ND $ $ " 21% " 9% $ " 10% $ " 6% Ritonavir ND ND ND ND $ $ " 370% " 618% Tenofovir " 6% " 10% $ $ $ $ $ # 15% $ # 14% *Denotes using caution and/or additional monitoring may be necessary when administering the respective medications together. Denotes a potentially dangerous combination of medications and that the concomitant administration of the agent(s) should be avoided. Administered as Atripla (efavirenz, emtricitabine, tenofovir DF) with ledipasvir 90 mg and sofosbuvir 400 mg. Abbreviations: AUC, area under the concentration curve; C max, maximal concentration; ND, no data; ", increase; #, decrease; $, negligible change. between DAAs and nucleotide reverse transcriptase inhibitors. Ledipasvir, which is coadministered in fixed dose combination with sofosbuvir, can increase the exposure of tenofovir; but coadministration of the two agents is not contraindicated. 7 Toxic concentrations of tenofovir can lead to irreversible renal toxicity. When sofosbuvir and ledipasvir were given in combination with tenofovir, supratherapeutic concentrations of tenofovir were only measured when given with the ritonavirboosted protease inhibitors atazanavir and darunavir. 11 Based on the limited available data, the interaction does not appear clinically relevant, but special consideration should be given when the combination is prescribed in those at higher risk for renal toxicity of tenofovir such as those with hypertension or diabetes. All other drug-drug interactions of DAAs with common HIV agents are either not well described in the literature or not believed to be clinically significant. Synthesis and Recommendations of HIV Agents Thoughtful use of HIV protease inhibitors is warranted as postmarketing data and clinical experience are gained. Tables (1 3) summarize the available literature for drug-drug interactions when giving DAAs with common antiretroviral agents. Concurrent administration of HIV protease inhibitors and DAAs poses several notable clinical challenges. The combination of a protease inhibitor with simeprevir can lead to significant alterations in exposure of simeprevir. We recommend against the use of simeprevir with any HIV protease inhibitor rather than adjusting the dose of simeprevir. The protease inhibitor tipranavir, administered with or without ritonavir, should not be coadministered with sofosbuvir or ledipasvir as the combination can result in subtherapeutic concentrations of the DAAs. We advocate against the use of efavirenz-containing HIV treatment regimens in combination with the 3D regimen or simeprevir. We prefer the fixed dose combination of ledipasvir and sofosbuvir for patients prescribed efavirenz as a component of the HIV treatment regimen. Further, etravirine, nevirapine, or delavirdine should not be administered concurrently with simeprevir. Ledipasvir and sofosbuvir appear to have fewer clinically significant drug interactions than the 3D regimen Table 2. Effect of Select HIV Antiviral Agents on the 3D Regimen Containing Ombitasvir, Dasabuvir, and Ritonavir 8 Paritaprevir (ABT450) Ombitasvir (ABT267) Dasabuvir (ABT333) Ritonavir C max AUC C max AUC C max AUC C max AUC Darunavir/ritonavir* # 30% # 41% # 24% # 27% # 16% # 27% " 61% " 28% Efavirenz ND ND ND ND ND ND ND ND Rilpivirine " 30% " 23% " 11% " 9% " 18% " 17% " 10% " 8% Tenofovir # 32% # 16% # 11% # 1% # 15% # 15% # 17% # 5% *Administered as darunavir 600 mg twice daily and ritonavir 100 mg daily. Coadministration of efavirenz with paritaprevir/ritonavir with dasabuvir led to premature study discontinuation for several subjects due to adverse events; thus, pharmacokinetic evaluations could not be performed. Denotes a potentially dangerous combination of medications and that the concomitant administration of the agent(s) should be avoided. Tenofovir administered in combination formulation with emtricitabine. Abbreviations: AUC, area under the concentration curve; C max, maximal concentration; ND, no data; ", increase; #, decrease.

4 HEPATOLOGY, Vol. 63, No. 2, 2016 DICK ET AL. 637 Table 3. Effect of New DAAs on Select HIV Antiviral Agents Darunavir/ritonavir Efavirenz Raltegravir Rilpivirine Ritonavir Tenofovir C max AUC C max AUC C max AUC C max AUC C max AUC C max AUC " 150%- " 7% " 13% Ribavirin ND ND ND ND " 16% "12% ND ND ND ND $ $ Ledipasvir 7 $ $ $ $ # 18% # 15% $ $ # 7%, " 5%, " 32%- 79%,,k " 40%- 98%,,k Sofosbuvir 6 $ $ $ $ # 43% # 27 $ $ $ $ " 25% # 2% Simeprevir 5 " 4%/" " 18%/ # 3% # 10% " 3% " 8% " 4% " 12% " 23%*, " 32%*, " 19% " 18% 23%* " 32%* Daclatasvir 9,10 ND # ND # ND # ND # ND ND ND ND ND ND # 5% " 10% 3D regimen 8 # 8-21% # 24%- Magnitude of " 133% " 134% " 116%- " 36% concentration changes not known. Increased hepatotoxicity risk. 200% 243% *The dose of simeprevir in this interaction study was 50 mg and is lower than the recommended 150 mg dose. Ledipasvir administered in combination with sofosbuvir 400 mg. Ritonavir administered in combination with atazanavir 300 mg/. Administered as Atripla (efavirenz, emtricitabine, tenofovir DF). k Administered as Complera (emtricitabine, rilpivirine, tenofovir DF). Denotes a potentially dangerous combination of medications and that the concomitant administration of the agent(s) should be avoided. # Denotes using caution and/or additional monitoring may be necessary when administering the respective medications together. Abbreviations: AUC, area under the concentration curve; C max, maximal concentration; ND, no data; ", increase; #, decrease; $, negligible change. and simeprevir. Raltegravir, efavirenz, and darunavir administered with ritonavir can alter drug concentrations of both ledipasvir and sofosbuvir; however, dose adjustments of ledipasvir or sofosbuvir are not required when coadministered with the aforementioned HIV treatment agents. Concurrent administration of tenofovir with ledipasvir can result in significant changes in tenofovir concentrations. The combination of tenofovir and ledipasvir does not warrant dose adjustment of either agent, but we recommend routine monitoring of renal function. Literature regarding drug interactions with common HIV agents in combination with daclatasvir or ribavirin is limited. Daclatasvir is a substrate of CYP3A4 and P- gp; therefore, we recommend against the use of daclatasvir concomitantly with HIV treatment agents that are strong or moderate inducers or inhibitors of CYP3A4 and P-gp. When administering daclatasvir with HIV agents that are substrates of or weakly inhibit or induce CYP3A4 or P-gp, we endorse judicious monitoring for toxicities of daclatasvir or the coadministered agent. Drug interactions between HIV agents and ribavirin are not thought to be clinically significant. Immunosuppressive Agents Managing HCV infection in transplant recipients has always been challenging. Many practitioners are apprehensive about using interferon-based therapies posttransplant as interferon can activate the immune system, theoretically making rejection more likely. 12 While DAAs do not carry the same risk of immune activation, they do carry significant risks of drug interactions. Calcineurin Inhibitors. Simeprevir concentrations are increased approximately six-fold when given concomitantly with cyclosporine. 5 The mechanism is thought to be mediated by inhibition of the organic anion transporter protein 1B1, P-gp, and CYP3A by cyclosporine. This interaction is different from most interactions with calcineurin inhibitors as the magnitude of change of simeprevir exposure is larger than the magnitude of change of cyclosporine. Cyclosporine s maximum concentration is increased 16% and the area under the curve is increased 20% when given concomitantly with simeprevir. We do not recommend dose-adjusting simeprevir; rather, we recommend avoiding concomitant administration of the two agents. 5 Tacrolimus does not increase the exposure of simeprevir to an extent that reaches clinical significance. However, tacrolimus s maximum concentration may decrease 24% and the area under the curve 17% when given concomitantly with simeprevir. 5 Judicious monitoring of tacrolimus concentrations is warranted when giving these two agents concomitantly. Importantly, at the end of simeprevir therapy, tacrolimus concentrations may increase by the same magnitude; therefore, obtaining a tacrolimus trough approximately 1 week after simeprevir is discontinued is recommended. Cyclosporine and tacrolimus alter the concentrations of daclatasvir and sofosbuvir, but these changes are not clinically significant. 6,9 Although the maximal concentrations and exposure of sofosbuvir are increased 2.5- fold and 4.5-fold, respectively, when given with cyclosporine, there are no apparent toxicities associated with increased sofosbuvir concentrations or its metabolites. Concomitant use of sofosbuvir, ledipasvir, or daclatasvir

5 638 DICK ET AL. HEPATOLOGY, February 2016 Table 4. Effect of Immunosuppressive Agents on new DAAs Daclatasvir 9 Ledipasvir 7 Sofosbuvir 6 Simeprevir 5 C max AUC C max AUC C max AUC C max AUC Cyclosporine " 4% " 40% ND ND " 154% " 353% " 374%* " 481%* Tacrolimus " 7% " 5% ND ND # 3% " 13% " 79% " 85% *Denotes a potentially dangerous combination of medications and that the concomitant administration of the agent(s) should be avoided. Abbreviations: AUC, area under the concentration curve; C max, maximal concentration; ND, no data; ", increase; #, decrease. Table 5. Effect of New DAAs on Immunosuppressive Agents Cyclosporine Tacrolimus Sirolimus Everolimus C max AUC C max AUC C max AUC C max AUC Ribavirin 25 $ $ $ $ $ $ $ $ Ledipasvir 7 $ $ ND ND ND ND ND ND Sofosbovir 6 $ $ # 27% " 9% ND ND ND ND Simeprevir 5 " 16% " 19% # 24% # 17% ND ND ND ND Daclatasvir 9 # 4% " 3% # 5% $ ND ND ND ND 3D regimen 8,17,18 " 1%* " 482%* " 299% " 5613% Magnitude of concentration changes not known. Expected increase in both C max and AUC. Magnitude of concentration changes not known. Expected i ncrease in both C max and AUC. *Denotes using caution and/or additional monitoring may be necessary when administering the respective medications together. Denotes a potentially dangerous combination of medications and that the concomitant administration of the agent(s) should be avoided. Abbreviations: AUC, area under the concentration curve; C max, maximal concentration; ND, no data; ", increase; #, decrease; $, negligible change. with either calcineurin inhibitor is considered safe based on current data. Tables 4 and 5 summarize the effects of these DAAs and immunosuppressant concentrations when given concomitantly. The 3D regimen contains ritonavir. Although doses of ritonavir employed in the 3D regimen are lower than those used in HIV therapy, significant interactions are expected when given concomitantly with either calcineurin inhibitor. Ritonavir is a potent inhibitor of the CYP3A system and P-gp and is known to interact with both cyclosporine and tacrolimus. 13,14 In combination with the 3D regimen, tacrolimus exposure is increased 57-fold, whereas cyclosporine exposure is increased approximately six-fold, necessitating empiric dose adjustments of both calcineurin inhibitors. 8 One prospective study in liver transplant recipients showed that the combination of the 3D regimen and a calcineurin inhibitor was utilized successfully with a low incidence of adverse events and no reported graft rejection episodes. 15 If the 3D regimen is used in combination with tacrolimus, we recommend a tacrolimus dose decrease to 0.5 mg by mouth once weekly, with further dose adjustments being made based upon serum concentrations. It is important to note that when administering tacrolimus concurrently with ritonavir, the pharmacokinetic curve of tacrolimus lacks an absorption peak every 12 hours. This results in a significantly lower area under the curve when compared with the pharmacokinetic curve of tacrolimus when not concurrently administered with ritonavir despite achieving similar tacrolimus trough concentrations. 16 This theoretically leads to an increased risk of allograft rejection. Conversely, cyclosporine doses should be decreased approximately 80%- 90% when starting 3D therapy. It is important to remember to increase tacrolimus and cyclosporine doses when discontinuing 3D therapy and to adjust Table 6. Effect of Immunosuppressive Agents on the 3D Regimen 8 Paritaprevir (ABT450) Ombitasvir (ABT267) Dasabuvir (ABT333) Ritonavir C max AUC C max AUC C max AUC C max AUC Cyclosporine " 44%* " 72%* # 1%* " 8%* # 34%* # 30%* # 10%* " 11%* Tacrolimus # 43% #34% # 7% #6% # 15% # 10% # 24% # 13% *Denotes using caution and/or additional monitoring may be necessary when administering the respective medications together. Denotes a potentially dangerous combination of medications and that the concomitant administration of the agent(s) should be avoided. Abbreviations: AUC, area under the concentration curve; C max, maximal concentration; ", increase; #, decrease.

6 HEPATOLOGY, Vol. 63, No. 2, 2016 DICK ET AL. 639 calcineurin inhibitor doses based upon serum concentrations. Tables 5 and 6 summarize the effects of concomitant administration with the 3D regimen and calcineurin inhibitors. Mammalian Target of Rapamycin Inhibitors. Limited data exist for concomitant use of sirolimus or everolimus with new DAAs. Sirolimus concentrations are not predictable when given concomitantly with simeprevir; therefore, monitoring serum concentrations of sirolimus is necessary. 5 The use of ritonavir, a component of the 3D regimen, with everolimus is not recommended due to an increased risk of everolimus concentrations and exposure. 17,18 We recommend avoiding this interaction and selecting an alternative regimen to manage HCV. If the therapies must be used concomitantly, we recommend empirically decreasing the dose of mammalian target of rapamycin inhibitor as much as possible, monitoring serum concentrations frequently, and using blood concentrations to guide dosing. Additional Consideration for Those With Immunosuppressive Agents. Finally, HCV clearance has been associated with improved hepatic function and an increased rate of clearance of hepatically metabolized immunosuppressive agents, including the calcineurin inhibitors. There have been multiple reports of immune-mediated allograft injury following sustained virological response in liver transplant recipients, with an overall prevalence of rejection following treatment of HCV of 6%. 19 We advocate careful monitoring of immunosuppression trough levels following completion of DAA therapy. Synthesis and Recommendations for Immunosuppressive Agents. Concomitant administration of calcineurin inhibitors and simeprevir can provide clinical challenges. We recommend avoiding concomitant administration of cyclosporine and simeprevir. Thoughtful monitoring of tacrolimus concentrations is necessary to maximize immunosuppressive goals both when starting and when discontinuing simeprevir therapy. At a minimum, we recommend obtaining a tacrolimus trough concentration 1 week after initiating and discontinuing simeprevir therapy. Both calcineurin inhibitors can be given concomitantly with sofosbuvir, ledipasvir, and daclatasvir. Again, routine monitoring of calcineurin inhibitor concentrations is recommended. Both sofosbuvir and 3D-based regimens are effective to eradicate HCV posttransplant. The 3D combination, however, leads to significant drug-drug interactions. We advise against the combination of 3D and calcineurin inhibitors when possible. If 3D therapy is used, an empiric decrease of tacrolimus to 0.5 mg by mouth once weekly is recommended at the start of 3D therapy. We recommend a tacrolimus concentration measured weekly initially to guide dosing. Cyclosporine doses should be decreased 80%-90% empirically when starting 3D therapy and trough concentrations obtained twice weekly initially to guide dosing. Doses of both calcineurin inhibitors must be increased when discontinuing 3D therapy. Frequent monitoring, two to three times weekly, will be necessary to determine the rate at which 3A4 inhibition is diminished by ritonavir clearance. Based on the pharmacokinetics of ritonavir, the effect of inhibition will start to diminish in the first day or two after discontinuing 3D therapy. We recommend trying to avoid mammalian target of rapamycin inhibitors with all DAAs if possible. However, if a mammalian target of rapamycin inhibitor must be used, everolimus may be the preferred agent, despite being labeled as contraindicated, because it has a shorter half-life than sirolimus and dose adjustments may be more readily noticed on laboratory evaluation. Everolimus concentrations should be assessed at least twice weekly to assess exposure, but sirolimus concentrations should not be drawn more often than once weekly due to its long half-life. Other Relevant Interactions Tables 7 and 8 summarize other known drug-drug interactions with DAAs, and it is likely that more drugdrug interactions will become apparent with postmarketing surveillance. Estrogen-Containing Products. Importantly, concomitant administration of ethinyl estradiol and the 3D regimen is contraindicated due to an increased risk of alanine aminotransferase elevations. 8 The exact mechanism of the interaction is not known, and other estrogens did not increase the risk of alanine aminotransferase elevation. However, because of the limited number of patients studied and a lack of postmarketing data, use extreme caution when administering any estrogen with the 3D regimen. We recommend stopping the estrogen product for at least 1 week prior to starting 3D, and therapy may be resumed 2 weeks after discontinuation of 3D. 8 Acid Suppressants. The solubility of ledipasvir decreases as ph increases; therefore, ledipasvir is particularly dependent upon acidic environments for absorption (Table 7). 7 Coadministration with proton-pump inhibitors (PPIs) is not recommended, and avoiding anti-acids within 4 hours of ledipasvir administration is important. The package label for ledipasvir states that concomitant administration with omeprazole 20 mg daily is safe. When omeprazole is coadministered with ledipasvir, concentrations of ledipasvir are not significantly decreased when given at the same time. However,

7 640 DICK ET AL. HEPATOLOGY, February 2016 Table 7. Relevant Drug-Drug Interactions Leading to Alterations in Drug Exposure Drug Exposure (C max and/or AUC) Drug/Drug Class DCV 9 Concomitant Concomitant Concomitant Concomitant Drug 9 LDV 7 Drug 7 SOF 6 Drug 6 SMV 5,28 Drug 5,28 Anticonvulsants Expected to # but ND* #* $* #* ND* #* $* ND to date* Antimycobacterials # ND # $ # $ # $ Azole antifungals " ND ND ND ND ND " $ Calcium channel blockers ND ND $ $ ND ND $ " Erythromycin ND ND ND ND ND ND " " HMG-CoA reductase inhibitors ND* "* $* "* ND* ND* $* "* Methadone $ $ ND ND $ $ $ $ Phosphodiesterase inhibitors ND ND ND ND ND ND $ " Proton pump inhibitors $ 8 ND # $ ND ND $ $ St. John s wort ND* ND* #* $* #* ND* #* $* Warfarin ND ND ND ND ND ND $ $ *Denotes using caution and/or additional monitoring may be necessary when administering the respective medications together. Drug exposure of omeprazole is increased when given in combination with simeprevir. Denotes a potentially dangerous combination of medications and that the concomitant administration of the agent(s) should be avoided. Abbreviations: AUC, area under the concentration curve; C max, maximal concentration; DCV, daclatasvir; HMG-CoA, 3-hydroxy-3-methyl-glutaryl-coenzyme A; LDV, ledipasvir; ND, no data; SMV, simeprevir; SOF, sofosbuvir; ", increase; #, decrease; $, negligible change. when omeprazole is administered 2 hours prior to ledipasvir administration, concentrations of ledipasvir are reduced by approximately 50% to concentrations where viral resistance may become a concern. 7 No published data are available for ledipasvir administration in those chronically taking a PPI or omeprazole doses greater than 20 mg daily. The half-life for the restoration of acid secretion is 24 hours for those taking omeprazole and 46 hours for pantoprazole. 20 Therefore, the duration of acid suppression in those on chronic PPIs may decrease the likelihood of ledipasvir absorption and increase the risk of viral resistance. Alternatively, famotidine was successfully given with ledipasvir in clinical trials, up to 20 mg by mouth twice daily. 21 We advocate famotidine use over PPIs and encourage administration of ledipasvir with an acidic juice to increase the likelihood of absorption. The same ph dependence is expected for Gilead s next-generation NS5A inhibitor, GS Importantly, other DAAs for HCV, including NS5A, NS5B, and protease inhibitors, are not dependent upon ph for drug absorption. Antiepileptics. Coadministration of phenytoin, carbamazepine, or phenobarbital with any of the DAAs in this review is expected to decrease the concentrations Table 8. Relevant Drug-Drug Interactions Leading to Alterations in Drug Exposure With the 3D Regimen 8,28 Drug Exposure (C max and/or AUC) Drug/Drug Class Paritaprevir (ABT450) Ombitasvir (ABT267) Dasabuvir (ABT333) Ritonavir Concomitant Drug Anticonvulsants* # # # # Variable Antimycobacterials ND ND ND # " Azole antifungals " k $ k " k " k #" k Calcium channel blockers # $ $ $ " Erythromycin ND ND ND ND ND HMG-CoA reductase inhibitors # "$ k $ k $ k $ k " k Methadone** ND ND ND ND #$ Phosphodiesterase inhibitors ND k ND k ND k ND k " k Proton pump inhibitors " $ $ $ # St. John s wort ND k ND k ND k ND k ND k Warfarin $ $ $ $ $ *Ritonavir increases drug exposure of carbamazepine; ritonavir decreases drug exposure of phenytoin. Denotes using caution and/or additional monitoring may be necessary when administering the respective medications together. Ritonavir increases drug exposure of rifabutin and rifabutin metabolite; rifampin decreases drug exposure of ritonavir. Ritonavir increases drug exposure of ketoconazole and itraconazole; ritonavir decreases drug exposure of voriconazole. k Denotes a potentially dangerous combination of medications and that the concomitant administration of the agent(s) should be avoided. Ritonavir increases drug exposure of clarithromycin. # Rosuvastatin increases drug exposure of ABT450. **Ritonavir decreases drug exposure of methadone; the 3D regimen has a negligible effect on drug exposure of methadone. Abbreviations: AUC, area under the concentration curve; C max, maximal concentration; HMG-CoA, 3-hydroxy-3-methyl-glutaryl-coenzyme A; ND, no data; ", increase; #, decrease; $, negligible change.

8 HEPATOLOGY, Vol. 63, No. 2, 2016 DICK ET AL. 641 and exposure to the anti-hcv agents through induction of the CYP3A system. St. John s wort and rifampin are also potent inducers of the CYP3A system and can lead to decreased exposure of the DAA. 8 The concomitant use of any of these inducing agents is not recommended. 5-8 Similar interactions are expected with daclatasvir. To complicate the interaction with the 3D regimen, ritonavir can also affect the same enzymes, leading to altered concentrations of the antiseizure agents. In general, it is best to avoid the complicated drug-drug interaction all together. Lipid-Lowering Agents. Gemfibrozil can increase the exposure of dasabuvir, a component of the 3D regimen, by 10-fold, which can increase the risk of QT prolongation. Concurrent administration with lovastatin and simvastatin is discouraged by the manufacturer; however, if monitoring for myopathy, the concurrent administration of any DAA with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors is likely safe. 8 Similarly, rosuvastatin, atorvastatin, and simvastatin concentrations can be increased when given concomitantly with simeprevir. 5 Rosuvastatin doses not to exceed 10 mg daily and atorvastatin at doses not to exceed 40 mg daily are recommended by the manufacturer of simeprevir. 5 Rosuvastatin concentrations may also be increased if given with sofosbuvir/ledipasvir, and its coadministration is discouraged. 7 If patients are concerned or if statin therapy can be held while undergoing HCV treatment, the statin can be resumed upon completing therapy. Phosphodiesterase Inhibitors. Sildenafil coadministration with 3D leads to an increased risk of sildenafil-associated adverse effects including visual disturbances, priapism, hypotension, and syncope. 8 Importantly, this was studied with higher doses for pulmonary arterial hypertension, and the interaction with doses used for erectile dysfunction is not clearly understood. The concomitant use of simeprevir with phosphodiesterase type 5 inhibitors can result in increased concentrations of the phosphodiesterase-5 inhibitor but are clinically manageable. Dose adjustment of a phosphodiesterase-5 inhibitor used to treat pulmonary hypertension may be needed, but it is unlikely that a patient using one of these agents for erectile dysfunction will experience adverse effects. 5 Cardiovascular Agents. Calcium channel blockers when given concomitantly with simeprevir or the 3D regimen can increase calcium channel blocker exposure through CYP3A4 and/or P-gp inhibition by simeprevir. 5,8 Clinical monitoring for hypotension and bradycardia are warranted, depending upon the calcium channel blocker used. Smaller doses of the calcium channel blocker are likely needed to achieve therapeutic goals. Postmarketing data show that sofosbuvir and ledipasvir or sofosbuvir in combination with another DAA when coadministered with amiodarone can lead to symptomatic bradycardia and in one case led to a fatal cardiac arrest. 6,7 In reported cases, bradycardia has occurred within hours and up to 2 weeks after starting the sofosbuvir-containing regimen. 22 Patients with no alternative therapy for amiodarone who will be coadministered a sofosbuvir-containing regimen should receive cardiac monitoring in an inpatient setting for at least 48 hours. Due to the long half-life of amiodarone, the time required between stopping amiodarone and beginning sofosbuvir is unknown. We recommend amiodarone be stopped for a minimum of 4-8 weeks prior to initiating sofosbuvir. Benzodiazepines. Simeprevir and the 3D regimen are known to increase the exposure of both oral midazolam and triazolam. The mechanism of interaction is thought to be through intestinal CYP3A4 inhibition. 5,8 The use of these agents is not contraindicated, but knowledge of this interaction will allow clinicians to give smaller doses of benzodiazepine and upwardly titrate until the desired effect is achieved. Because of the increased exposure of the benzodiazepine, it is possible that sedation may persist longer than expected; and patients should be monitored for prolonged sedation. Intravenous administration or other benzodiazepines, such as lorazepam or diazepam, should be considered when benzodiazepines are necessary. Azole Antifungal Agents. Azole antifungal agents can increase the concentrations of simeprevir through CYP3A inhibition, and concomitant use is not recommended. 5 However, this may not be clinically feasible in all situations. Diligent monitoring of adverse effects and pharmacodynamic interactions, such as QTc prolongation, is warranted if the agents are administered concomitantly. It may be necessary to change from simeprevir to an alternative agent if an azole antifungal is clinically indicated. Daclatasvir concentrations are also expected to increase when given with azole antifungals, but the magnitude of the interaction and clinical significance are not yet known. Synthesis and Recommendations for Other Relevant Interactions. It is almost certain postmarketing surveillance will identify more clinically significant drug interactions. We recommend close monitoring for drug interactions of medications metabolized through the CYP450 enzyme system because the chance of interactions is more significant. Patients should refrain from all herbal and dietary supplements due to a lack of drug

9 642 DICK ET AL. HEPATOLOGY, February 2016 interaction data with these substances, unless testing has shown its safety. We recommend stopping herbals and dietary supplements at least 1 week prior to starting therapy. We recommend discontinuing PPIs at least 1 week prior to starting ledipasvir therapy. The package label for sofosbuvir/ledipasvir suggests that famotidine doses of 40 mg by mouth twice daily can be given. 10 However, famotidine was given up to doses of 20 mg by mouth twice daily in clinical trials. 21 We recommend not giving doses greater than 20 mg by mouth twice daily based on the design of clinical trials. Additionally, we recommend separating administration of ledipasvir and famotidine by 4 hours and giving ledipasvir with orange or tomato juice to increase the likelihood of absorption. We discourage coadministration of the antiseizure medications phenytoin, carbamazepine, and phenobarbital with DAAs if possible. However, if HCV treatment with any of the DAAs is required, we recommend evaluating the use of levetiracetam in place of the interacting antiseizure medications in consultation with a neurologist. For any patient switched to levetiracetam, all other antiseizure medications should be discontinued at least 1 week prior to starting a DAA. Although clinical decision-support software is available in the hospital and community to prevent drug interactions, these systems often miss important interactions or lead to alert fatigue. 23 Drug interaction software should augment the clinicians decision making of clinically significant drug interactions. Strategies to avoid clinically significant drug interactions should include a detailed medication history, including over-the-counter medications, herbals, and dietary supplements. Additionally, we recommend using drug interaction resources, such as and www. hcvdruginfo.ca. Specific antiretroviral interactions can be found at Finally, drug information resources, including com, and require subscriptions but contain valuable data and tools to screen for specific drug-drug interactions. Summary The recent series of US Food and Drug Administration approvals of highly effective and well-tolerated DAAs for the treatment of chronic HCV infection has led to a dramatic surge in the number of patients with HCV who are willing and able to be treated as well as in the number of providers to treat HCV infection. New DAAs can routinely achieve 95% effective cure rates regardless of HCV genotype. Although treatment of chronic HCV infection has become simpler and more effective, nuances to therapy remain, particularly for drug-drug interactions. The potential for important drug-drug interactions increases with the complexity of the DAA regimen employed. Critical interactions exist for DAAs with many commonly prescribed and overthe-counter agents, e.g., greatly decreased absorption of ledipasvir in the setting of PPI therapy. The great majority of drug-drug interactions are manageable and do not present an absolute barrier to safe and effective treatment of HCV infection. Nonetheless, as DAAs can be both the victim and the cause of drug-drug interactions, detailed and thorough evaluation of potential drug-drug interactions is needed before, during, and after DAA therapy for HCV infection. Acknowledgment: We thank Jill Rhead for Fig. 1. References 1. US Food and Drug Administration. Preventable adverse reactions: a focus on drug interactions. Last updated June 18, Accessed January Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet 2000;38: Marquez B, Van Bambeke F. 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10 HEPATOLOGY, Vol. 63, No. 2, 2016 DICK ET AL van Maarseveen E, Crommelin H, Mudrikova T, van den Broek MPH, van Zuilen AD. Pretransplantation pharmacokinetic curves of tacrolimus in HIV-infected patients on ritonavir-containing cart: a pilot study. Transplantation 2013;95: Zortress [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp.; Rapamune [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals, Inc.; Berenguer M. Systematic review of the treatment of established recurrent hepatitis C with pegylated interferon in combination with ribavirin. J Hepatol 2008;49: Shin JM, Sachs G. Pharmacology of proton pump inhibitors. Curr Gastroenterol Rep 2008;10: Afhal N, Reddy R, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014;370: US Food and Drug Administration. FDA Drug Safety Communication: FDA warns of serious slowing of the heart rate when antiarrhythmic drug amiodarone is used with hepatitis C treatments containing sofosbuvir (Harvoni) or Sovaldi in combination with another direct acting antiviral drug. htm. Published March 24, Accessed April Tannenbaum C, Sheehan N. Understanding and preventing drug-drug and drug-gene interactions. Expert Rev Clin Pharmacol 2014;7: Ouwerkerk-Mahadevan S, Sekar V, Simion A, Peeters M, Beaumont- Mauviel M. The pharmacokinetic interactions of the HCV protease inhibitor simeprevir (TMC435) with HIV antiretroviral agents in healthy volunteers [Abstract]. Presented at: Infectious Diseases Week; October 17-21, 2012; San Diego, CA. Abstract Copegus [package insert]. South San Francisco, CA: Genentech, Inc.; Ramanathan S, Cheng A, Mittan A, Ebrahimi R, Kearney BP. Absence of clinically relevant pharmacokinetic interaction between ribavirin and tenofovir in healthy subjects. J Clin Pharmacol 2006;46: Beumont-Mauviel M, Simion A, De Smedt G, Spittaels K, Peeters M, Sekar V. The pharmacokinetic interaction between the investigational NS3-4A HCV protease inhibitor TMC435 and methadone [Abstract]. HEPATOLOGY 2011;54(Suppl. 1):1000A. Abstract Norvir [package insert]. North Chicago, IL: AbbVie, Inc.; 2013.