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Drug–Drug Interaction Profile of the Fixed-Dose Combination Tablet Regimen Ledipasvir/Sofosbuvir

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Abstract

Ledipasvir/sofosbuvir (Harvoni®), a fixed-dose combination tablet of an NS5A inhibitor ledipasvir and an NS5B polymerase inhibitor sofosbuvir, is approved for the treatment of chronic hepatitis C virus infection. Ledipasvir/sofosbuvir exhibits a favorable drug–drug interaction profile and can be administered with various medications that may be used by hepatitis C virus-infected patients, including patients with comorbidities, such as co-infection with human immunodeficiency virus or immunosuppression following liver transplantation. Ledipasvir/sofosbuvir is not expected to act as a victim or perpetrator of cytochrome P450- or UDP-glucuronosyltransferase 1A1-mediated drug–drug interactions. With the exception of strong inducers of P-glycoprotein, such as rifampin, ledipasvir/sofosbuvir is not expected to act as a victim of clinically relevant drug–drug interactions. As a perpetrator of pharmacokinetic drug–drug interactions via P-glycoprotein/BCRP, ledipasvir/sofosbuvir should not be used with rosuvastatin and elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate, whereas its co-administration with amiodarone is not recommended because of a pharmacodynamic interaction. This review summarizes a number of drug interaction studies conducted in support of the clinical development of ledipasvir/sofosbuvir.

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References

  1. SOVALDI®, Gilead Sciences Inc. SOVALDI® (sofosbuvir) tablets, for oral use. US Prescribing Information. Foster City, CA. Revised April 2017.

  2. SOVALDI®, Gilead Sciences International Ltd. SOVALDI® (sofosbuvir) Tablets, (400 mg sofosbuvir) Antiviral Agent. Product Monograph. Mississauga, Canada. Revised 26 July 2016.

  3. SOVALDI®, Gilead Sciences International Ltd. Sovaldi® 400 mg film-coated tablets. Summary of Product Characteristics (SmPC). Cambridge, United Kingdom. Revised March 2017.

  4. HARVONI®, Gilead Sciences Inc. HARVONI® (ledipasvir and sofosbuvir) tablets, for oral use. US Prescribing Information. Foster City, CA. Revised April 2017.

  5. HARVONI®, Gilead Sciences Inc. HARVONI® (ledipasvir and sofosbuvir) 90 mg/400 mg tablets for oral use. Summary of Product Characteristics (SmPC). Cambridge, United Kingdom. Revised June 2017.

  6. HARVONI®, Gilead Sciences Canada I. PrHARVONI® (ledipasvir and sofosbuvir) 90 mg/400 mg tablets for oral use. Summary of Product Characteristics (SmPC). Mississauga, Ontario. Revised 23 May 2017.

  7. HARVONI®, Gilead Sciences KK. HARVONI® (ledipasvir/sofosbuvir) Combination Tablets. Japan Package Insert [Japanese]. Version 6. Tokyo, Japan. Revised April 2017.

  8. German P, Mathias A, Brainard D, Kearney BP. Clinical pharmacokinetics and pharmacodynamics of ledipasvir/sofosbuvir, a fixed-dose combination tablet for the treatment of hepatitis C. Clin Pharmacokinet. 2016;55:1337–51.

    Article  CAS  PubMed  Google Scholar 

  9. Kirby BJ, Symonds WT, Kearney BP, Mathias AA. Pharmacokinetic, pharmacodynamic, and drug-interaction profile of the hepatitis C virus NS5B polymerase inhibitor sofosbuvir. Clin Pharmacokinet. 2015;54:677–90.

    Article  CAS  PubMed  Google Scholar 

  10. German P, Mathias A, Pang PS, et al. Lack of clinically significant pharmacokinetic drug-drug interaction between sofosbuvir (GS-7977) and GS-5885 or GS-9669 in healthy volunteers [Poster 1888]. In: 63rd Annual Meeting of the American Association for the Study of Liver Diseases; 2012 November 9–13; Boston: Gilead Sciences, Inc.; 2012.

  11. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014;370:1483–93.

    Article  CAS  PubMed  Google Scholar 

  12. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370:1889–98.

    Article  Google Scholar 

  13. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370:1879–88.

    Article  Google Scholar 

  14. German P, Pang PS, Fang L, Chung D, Mathias A. Drug-drug interaction profile of the fixed-dose combination tablet ledipasvir/sofosbuvir [Presentation #1976]. In: The 65th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting (AASLD); 2014 November 07–11; Boston.

  15. Garrison KL, Wang Y, Brainard DM, Sajwani K, Mathias A. The Effect of Rifampin on the Pharmacokinetics of Sofosbuvir in Healthy Volunteers [Poster 992]. In: The 65th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting (AASLD); 2014 November 07–11; Boston.

  16. German P, Garrison K, Pang PS, et al. Drug interactions between the anti-HCV regimen ledipasvir/sofosbuvir and ritonavir boosted protease inhibitors plus emtricitabine/tenofovir DF [Presentation 82]. In: Conference on Retroviruses and Opportunistic Infections; 2015 February 23–26; Seattle.

  17. German P, Moorehead L, Pang P, Vimal M, Mathias A. Lack of a clinically important pharmacokinetic interaction between sofosbuvir or ledipasvir and hormonal oral contraceptives norgestimate/ethinyl estradiol in HCV-Uninfected female subjects. J Clin Pharmacol. 2014;54:1290–8.

    Article  CAS  PubMed  Google Scholar 

  18. Deng S, Chen XP, Cao D, et al. Effects of a concomitant single oral dose of rifampicin on the pharmacokinetics of pravastatin in a two-phase, randomized, single-blind, placebo-controlled, crossover study in healthy chinese male subjects. Clin Ther. 2009;31:1256–63.

    Article  CAS  PubMed  Google Scholar 

  19. Au NT, German P, Li Y, et al. Lack of an effect of ledipasvir on CYP3A activity in healthy volunteers [Poster P_47]. In: 17th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy; 2016 08–10 June; Washington, DC.

  20. German P, Mathias A, Brainard DM, Song Q, Ling J, Kearney BP. A thorough QT study to evaluate the effects of supratherapeutic doses of ledipasvir on the QTc interval in healthy subjects. Clin Pharmacol Drug Dev. 2017.

  21. PROGRAF®, Astellas Ireland Co Ltd. PROGRAF® (tacrolimus) capsules 0.5 mg/1 mg/5 mg, (tacrolimus) injection, (for intravenous use) 5 mg/mL. US Prescribing Information. County Kerry, Ireland. Revised May 2015.

  22. Novartis Pharmaceuticals Corporation. NEORAL® Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED; NEORAL® Oral Solution (cyclosporine oral solution, USP) MODIFIED. US Prescribing Information. East Hanover. Revised October 2009.

  23. Mathias A, Cornpropst M, Clemons D, Denning J, Symonds WT. No clinically significant pharmacokinetic drug-drug interactions between sofosbuvir (GS-7977) and the immunosuppressants cyclosporine A or tacrolimus in healthy volunteers [Poster 1869]. In: 63rd Annual Meeting of the American Association for the Study of Liver Diseases; 2012 November 9–13; Boston.

  24. Fernandez-Ruiz M, Polanco N, Garcia-Santiago A, et al. Impact of anti-HCV direct antiviral agents on graft function and immunosuppressive drug levels in kidney transplant recipients: a call to attention in the mid-term follow-up in a single-center cohort study. Transpl Int. 2018.

  25. Smolders EJ, Pape S, de Kanter CT, van den Berg AP, Drenth JP, Burger DM. Decreased tacrolimus plasma concentrations during HCV therapy: a drug-drug interaction or is there an alternative explanation? Int J Antimicrob Agents. 2017;49:379–82.

    Article  CAS  PubMed  Google Scholar 

  26. Abdel-Razzak Z, Loyer P, Fautrel A, et al. Cytokines down-regulate expression of major cytochrome P-450 enzymes in adult human hepatocytes in primary culture. Mol Pharmacol. 1993;44:707–15.

    CAS  PubMed  Google Scholar 

  27. Muntane-Relat J, Ourlin JC, Domergue J, Maurel P. Differential effects of cytokines on the inducible expression of CYP1A1, CYP1A2, and CYP3A4 in human hepatocytes in primary culture. Hepatology. 1995;22:1143–53.

    Article  CAS  PubMed  Google Scholar 

  28. Astellas Pharma US Inc. PROGRAF® tacrolimus capsules; tacrolimus injection (for intravenous infusion only). US Prescribing Information. Deerfield. Revised August 2009.

  29. Samuel D, Manns M, Forns X, et al. Ledipasvir/Sofosbuvir with ribavirin is safe in >600 decompensated and post-liver transplantation patients with HCV infection: an integrated safety analysis of the SOLAR-1 and SOLAR-2 trials. In: European Association for the Study of the Liver (EASL) The 50th International Liver Congress; 2015 April 22–26; Vienna, Austria.

  30. Gane E, Manns M, McCaughan G, et al. Ledipasvir/sofosbuvir with ribavirin in patients with decompensated cirrhosis or liver transplantation and HCV infection: SOLAR-1 and -2 Trials [Poster 1049]. In: American Association for the Study of Liver Diseases (AASLD); 2015 13–17 November; San Francisco.

  31. Garrison KL, German P, Arterburn S, et al. Pharmacokinetic analyses of ledipasvir/sofosbuvir in HCV-infected subjects with advanced liver disease and/or following liver transplantation [Poster SAT-198]. In: European Association of the Study of Liver Disease (EASL); 2016 13–17 April; Barcelona, Spain.

  32. Genentech Inc. COPEGUS® (ribavirin, USP) TABLETS. US Prescribing Information. Roche Laboratories Inc., Nutley. Revised February 2013.

  33. Aspinall EJ, Corson S, Doyle JS, et al. Treatment of hepatitis C virus infection among people who are actively injecting drugs: a systematic review and meta-analysis. Clin Infect Dis. 2013;57(Suppl 2):S80–9.

    Article  PubMed  Google Scholar 

  34. Mallinckrodt Inc. METHADOSE—methadone hydrochloride tablet. US Prescribing Information. St. Louis. Rev April. 2009.

  35. Kristensen K, Christensen CB, Christrup LL. The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine. Life Sci 1995;56:PL45–50.

    Article  Google Scholar 

  36. Kharasch ED, Bedynek PS, Park S, Whittington D, Walker A, Hoffer C. Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics: I. Evidence against CYP3A mediation of methadone clearance. Clin Pharmacol Ther. 2008;84:497–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Totah RA, Sheffels P, Roberts T, Whittington D, Thummel K, Kharasch ED. Role of CYP2B6 in stereoselective human methadone metabolism. Anesthesiology. 2008;108:363–74.

    Article  CAS  PubMed  Google Scholar 

  38. Denning J, Compropst M, Clemons D, et al. Lack of effect of the nucleotide analog polymerase inhibitor PSI-7977 on methadone PK and PD [Poster #372]. In: 62nd Annual Meeting of the Meeting of the American Association for the Study of Liver Diseases (AASLD); 2011 November 4–8; San Francisco, CA.

  39. Alter MJ. Epidemiology of viral hepatitis and HIV co-infection. J Hepatol. 2006;44:S6–9.

    Article  PubMed  Google Scholar 

  40. American Association for the Study of Liver Diseases (AASLD), Infectious Disease Society of America (IDSA). HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. Available at: https://hcvguidelines.org/. Accessed 21 Sept 2017.

  41. Chen TY, Ding EL, Seage Iii GR, Kim AY. Meta-analysis: increased mortality associated with hepatitis C in HIV-infected persons is unrelated to HIV disease progression. Clin Infect Dis. 2009;49:1605–15.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Lo Re V 3rd, Kallan MJ, Tate JP, et al. Hepatic decompensation in antiretroviral-treated patients co-infected with HIV and hepatitis C virus compared with hepatitis C virus-monoinfected patients: a cohort study. Ann Intern Med. 2014;160:369–79.

    PubMed  Google Scholar 

  43. Fierer DS, Uriel AJ, Carriero DC, et al. Liver fibrosis during an outbreak of acute hepatitis C virus infection in HIV-infected men: a prospective cohort study. J Infect Dis. 2008;198:683–6.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Kirk GD, Mehta SH, Astemborski J, et al. HIV, age, and the severity of hepatitis C virus-related liver disease: a cohort study. Ann Intern Med. 2013;158:658–66.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Thein HH, Yi Q, Dore GJ, Krahn MD. Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression. Hepatology. 2008;48:418–31.

    Article  Google Scholar 

  46. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL. Accessed 15 Aug 2016.

  47. Bristol-Myers Squibb Company. SUSTIVA® (efavirenz) capsules and tablets for oral use. US Prescribing Information. Princeton. Revised May 2014.

  48. Tibotec Pharmaceuticals. Edurant (rilpivirine) Tablets. US Prescribing Information. Raritan. Revised August 2012.

  49. Mouly S, Lown KS, Kornhauser D, et al. Hepatic but not intestinal CYP3A4 displays dose-dependent induction by efavirenz in humans. Clin Pharmacol Ther. 2002;72:1–9.

    Article  CAS  PubMed  Google Scholar 

  50. Tong L, Phan TK, Robinson KL, et al. Effects of human immunodeficiency virus protease inhibitors on the intestinal absorption of tenofovir disoproxil fumarate in vitro. Antimicrob Agents Chemother. 2007;51:3498–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. TRUVADA®, Gilead Sciences Inc. TRUVADA® (emtricitabine/tenofovir disoproxil fumarate) tablets, for oral use. US Prescribing Information. Foster City. Revised April 2017.

  52. German P, Pang PS, West, S., Han L, Sajwani K, Mathias S. Drug interactions between direct-acting anti-HCV antivirals sofosbuvir and ledipasvir and HIV antiretrovirals [Presentation 06]. In: 15th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy; 2014 May 19–21; Washington, DC.

  53. ATRIPLA®, Bristol Myers Squibb and Gilead Sciences Limited. ATRIPLA® (efavirenz/emtricitabine/tenofovir disoproxil fumarate) tablets, for oral use. US Prescribing Information. Foster City. Revised April 2017.

  54. COMPLERA®, Gilead Sciences Inc. COMPLERA® (emtricitabine, rilpivirine, tenofovir disoproxil fumarate) tablets, for oral use. US Prescribing Information. Foster City. Revised April 2017.

  55. ISENTRESS®, Merck Sharp & Dohme Corp. ISENTRESS® (raltegravir) film-coated tablets, for oral use. ISENTRESS® HD (raltegravir) film-coated tablets, for oral use ISENTRESS® (raltegravir) chewable tablets, for oral use. ISENTRESS® (raltegravir) for oral suspension. US Prescribing Information (USPI). Whitehouse Station. 2018.

  56. TIVICAY®, GlaxoSmithKline. TIVICAY® (dolutegravir) tablets, for oral use. US Prescribing Information. Research Triangle Park. Revised March 2017.

  57. Garrison KL, Custodio JM, Pang PS, et al. Drug Interactions between anti-HCV antivirals ledipasvir/sofosbuvir and integrase strand transfer inhibitor-based regimens [Poster 71]. In: 16th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy; 2015 26–28 May; Washington, DC.

  58. Kirby B, Mathias A, Rossi S, Moyer C, Shen G, Kearney BP. No clinically significant pharmacokinetic interactions between sofosbuvir (GS-7977) and HIV antiretrovirals atripla, rilpivirine, darunavir/ritonavir, or raltegravir in healthy volunteers [Poster 1877]. In: 63rd Annual Meeting of the American Association for the Study of Liver Diseases; 2012 November 9–13; Boston, Massachusetts.

  59. Iwamoto M, Wenning LA, Petry AS, et al. Minimal effects of ritonavir and efavirenz on the pharmacokinetics of raltegravir. Antimicrob Agents Chemother. 2008;52:4338–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hanley WD, Wenning LA, Moreau A, et al. Effect of tipranavir-ritonavir on pharmacokinetics of raltegravir. Antimicrob Agents Chemother. 2009;53:2752–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Naggie S, Cooper C, Saag M, et al. Ledipasvir and sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med. 2015:705–13.

  62. German P, Ni L, Stamm LM, et al. Pharmacokinetic analyses of ledipasvir/sofosbuvir and HIV antiretroviral regimens in subjects with HCV/HIV coinfection [Poster 1133]. In: American Association for the Study of Liver Diseases (AASLD); 2015 13–17 November; San Francisco, CA.

  63. Janssen-Cilag International NV. PREZISTA 800 mg film coated tablets. Summary of Product Characteristics. Beerse. Revised September 2015.

  64. Bristol-Myers Squibb Pharma EEIG. REYATAZ 300 mg hard capsules: Summary of Product Characteristics. Uxbridge. 2011.

  65. European Medicines Agency (EMA). Prezista: EPAR—Scientific Discussion European Public Assessment Report. 2006.

  66. REYATAZ®, Bristol-Myers Squibb Company. REYATAZ® (atazanavir) capsules, for oral use, REYATAZ® (atazanavir) oral powder. US Prescribing Information (USPI). Princeton. Revised October 2017.

  67. Gilead Sciences Ltd. Genvoya (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets, for oral use U.S. Prescribing Information. Foster City. Revised September 2017.

  68. Gilead Sciences Inc. STRIBILD® (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) tablets, for oral use. U.S. Prescribing Information. Foster City. Revised July 2015.

  69. Birkus G, Bam R, Frey C, et al. Intracellular activation pathways for GS-7340 and the effect of antiviral protease inhibitors [Poster #577]. In: Presented at 19th Conference on Retroviruses and Opportunistic Infections (CROI); 2012 March 5–8; Seattle.

  70. Lee WA, He G-X, Eisenberg E, et al. Selective intracellular activation of a novel prodrug of the human immunodeficiency virus reverse transcriptase inhibitor tenofovir leads to preferential distribution and accumulation in lymphatic tissue. Antimicrob Agents Chemother. 2005;49:1898–906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ruane PJ, Dejesus E, Berger D, et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of tenofovir alafenamide as 10-day monotherapy in HIV-1-positive adults. J Acquir Immune Defic Syndr. 2013;63:449–55.

    Article  CAS  PubMed  Google Scholar 

  72. Kirby B, Li H, Kearney BP, Mathias A. Population pharmacokinetics analysis of ledipasvir (GS-5885) in healthy and hepatitis C virus-infected subjects [Presentation of Poster P_33]. In: 15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy; 2014 19–21 May; Washington, DC.

  73. Kirby B, Gordi T, Symonds WT, Kearney BP, Mathias A. Population pharmacokinetics of sofosbuvir and its major metabolite (GS-331007) in healthy and HCV-infected adult subjects [Poster 1106]. In: The Liver Meeting® 2013 The 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2013 November 1–5; Washington DC.

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  1. Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA

    Polina German, Anita Mathias, Diana M. Brainard & Brian P. Kearney

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  1. Polina German
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  2. Anita Mathias
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Correspondence to Polina German.

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Gilead Sciences, Inc. provided funding for the research presented in this article.

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Polina German, Anita Mathias, Diana Brainard, and Brian P. Kearney are employees of Gilead, contributed significantly to the design, conduct, analyses, and interpretation of data, and were involved in the preparation, review, and approval of this article. Polina German, Anita Mathias, Diana Brainard, and Brian P. Kearney are stockholders of Gilead Sciences, Inc.

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The study protocol and informed consent documents were reviewed and approved by a duly constituted institutional review board before study initiation in accordance with the basic principles defined in the US 21 CFR Part 312.20 and the principles enunciated in the Declaration of Helsinki.

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German, P., Mathias, A., Brainard, D.M. et al. Drug–Drug Interaction Profile of the Fixed-Dose Combination Tablet Regimen Ledipasvir/Sofosbuvir. Clin Pharmacokinet 57, 1369–1383 (2018). https://doi.org/10.1007/s40262-018-0654-5

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