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Viral Hepatitis C Therapy: Pharmacokinetic and Pharmacodynamic Considerations

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Abstract

Chronic hepatitis C is a global health problem. To prevent or reduce complications, the hepatitis C virus (HCV) infection needs to be eradicated. There have been several developments in treating these patients since the discovery of the virus. As of 1 January 2014, the drugs that are approved for treatment of chronic HCV infection are peginterferon-α, ribavirin, boceprevir, telaprevir, simeprevir and sofosbuvir. In this review we provide an overview of the clinical pharmacokinetic characteristics of these agents by describing their absorption, distribution, metabolism and excretion. In the pharmacodynamic part we summarize what is known about the relationships between the pharmacokinetics of each drug and efficacy or toxicity. We briefly discuss the pharmacokinetics and pharmacodynamics of chronic hepatitis C treatment in special patient populations, such as patients with liver cirrhosis, renal insufficiency or HCV/HIV coinfection, and children. With this knowledge, physicians, pharmacists, nurse practitioners, etc. should be educated to safely and effectively treat HCV-infected patients.

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References

  1. Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect. 2011;17(2):107–15.

    PubMed  CAS  Google Scholar 

  2. Afdhal NH. The natural history of hepatitis C. Semin Liver Dis. 2004;24(Suppl 2):3–8.

    PubMed  Google Scholar 

  3. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347(13):975–82.

    PubMed  CAS  Google Scholar 

  4. Khuroo MS, Khuroo MS, Dahab ST. Meta-analysis: a randomized trial of peginterferon plus ribavirin for the initial treatment of chronic hepatitis C genotype 4. Aliment Pharmacol Ther. 2004;20(9):931–8.

    PubMed  CAS  Google Scholar 

  5. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358(9286):958–65.

    PubMed  CAS  Google Scholar 

  6. Zeuzem S, Hultcrantz R, Bourliere M, Goeser T, Marcellin P, Sanchez-Tapias J, et al. Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3. J Hepatol. 2004;40(6):993–9.

    PubMed  CAS  Google Scholar 

  7. Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364(13):1195–206.

    PubMed Central  PubMed  CAS  Google Scholar 

  8. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364(25):2405–16.

    PubMed  CAS  Google Scholar 

  9. FDA. Olysio prescribing information. 2013. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/205123s001lbl.pdf. Accessed 19 March 2014.

  10. FDA. Sovaldi prescribing information. 2013. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204671s000lbl.pdf. Accessed 19 March 2014.

  11. EMA. Sovaldi; product information. 2014. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002798/WC500160597.pdf. Accessed 19 March 2014.

  12. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol. 2011;55(2):245–64.

    Google Scholar 

  13. Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology (Baltimore, Md). 2009;49(4):1335–74.

  14. Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB; American Association for Study of Liver Diseases. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology (Baltimore, Md). 2011;54(4):1433–44.

  15. European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatitis C virus infection. J Hepatol. 2014;60(1):392–420.

    Google Scholar 

  16. Lamers MH, Broekman MM, Boucher CA, Brouwer JT, Burger DM, van Hoek B, et al. Treatment of hepatitis C monoinfection in adults—Dutch national guidelines. Neth J Med. 2013;71(7):377–85.

    PubMed  CAS  Google Scholar 

  17. Sen GC. Viruses and interferons. Annu Rev Microbiol. 2001;55:255–81.

    PubMed  CAS  Google Scholar 

  18. Feld JJ, Hoofnagle JH. Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature. 2005;436(7053):967–72.

    PubMed  CAS  Google Scholar 

  19. Sidwell RW, Huffman JH, Khare GP, Allen LB, Witkowski JT, Robins RK. Broad-spectrum antiviral activity of Virazole: 1-beta-d-ribofuranosyl-1,2,4-triazole-3-carboxamide. Science (New York, NY). 1972;25;177(4050):705–6.

  20. Paeshuyse J, Dallmeier K, Neyts J. Ribavirin for the treatment of chronic hepatitis C virus infection: a review of the proposed mechanisms of action. Curr Opin Virol. 2011;1(6):590–8.

    PubMed  CAS  Google Scholar 

  21. Kim CW, Chang KM. Hepatitis C virus: virology and life cycle. Clin Mol Hepatol. 2013;19(1):17–25.

    PubMed Central  PubMed  CAS  Google Scholar 

  22. Venkatraman S. Discovery of boceprevir, a direct-acting NS3/4A protease inhibitor for treatment of chronic hepatitis C infections. Trends Pharmacol Sci. 2012;33(5):289–94.

    PubMed  CAS  Google Scholar 

  23. Perni RB, Almquist SJ, Byrn RA, Chandorkar G, Chaturvedi PR, Courtney LF, et al. Preclinical profile of VX-950, a potent, selective, and orally bioavailable inhibitor of hepatitis C virus NS3-4A serine protease. Antimicrob Agents Chemother. 2006;50(3):899–909.

    PubMed Central  PubMed  CAS  Google Scholar 

  24. Lin TI, Lenz O, Fanning G, Verbinnen T, Delouvroy F, Scholliers A, et al. In vitro activity and preclinical profile of TMC435350, a potent hepatitis C virus protease inhibitor. Antimicrob Agents Chemother. 2009;53(4):1377–85.

    PubMed Central  PubMed  CAS  Google Scholar 

  25. Bartenschlager R, Lohmann V, Penin F. The molecular and structural basis of advanced antiviral therapy for hepatitis C virus infection. Nat Rev Microbiol. 2013;11(7):482–96.

    PubMed  CAS  Google Scholar 

  26. Sofia MJ, Bao D, Chang W, Du J, Nagarathnam D, Rachakonda S, et al. Discovery of a beta-d-2’-deoxy-2’-alpha-fluoro-2’-beta-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus. J Med Chem. 2010;53(19):7202–18.

    PubMed  CAS  Google Scholar 

  27. FDA. Roferon-A prescribing information. 2006. http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/103145s5060LBL.pdf. Accessed 9 July 2013.

  28. FDA. Intron A prescribing information. 2011. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/103132s5161lbl.pdf. Accessed 9 July 2013.

  29. Reddy KR. Development and pharmacokinetics and pharmacodynamics of pegylated interferon alfa-2a (40 kD). Semin Liver Dis. 2004;24(Suppl 2):33–8.

    PubMed  CAS  Google Scholar 

  30. Pedder SC. Pegylation of interferon alfa: structural and pharmacokinetic properties. Semin Liver Dis. 2003;23(Suppl 1):19–22.

    PubMed  Google Scholar 

  31. Thomas T, Foster G. Nanomedicines in the treatment of chronic hepatitis C—focus on pegylated interferon alpha-2a. Int J Nanomed. 2007;2(1):19–24.

    CAS  Google Scholar 

  32. Foster GR. Review article: pegylated interferons: chemical and clinical differences. Aliment Pharmacol Ther. 2004;20(8):825–30.

    PubMed  CAS  Google Scholar 

  33. EMA. PegIntron product information. 2014. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000280/WC500039388.pdf. Accessed 19 March 2014.

  34. EMA. Pegasys product information. 2013. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000395/WC500039195.pdf. Accessed 19 March 2014.

  35. FDA. Pegasys prescribing information. 2013. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/103964s5245lbl.pdf. Accessed 19 March 2014.

  36. FDA. PegIntron prescribing information. 2013. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/103949s5259lbl.pdf. Accessed 19 March 2014.

  37. Caliceti P. Pharmacokinetics of pegylated interferons: what is misleading? Dig liver Dis. 2004;36(Suppl 3):S334–9.

    PubMed  CAS  Google Scholar 

  38. Brennan BJ, Morcos PN, Wang K, Blotner SD, Morrison R, Hagedorn CH, et al. The pharmacokinetics of peginterferon alfa-2a and ribavirin in African American, Hispanic and Caucasian patients with chronic hepatitis C. Aliment Pharmacol Ther. 2012;35(10):1209–20.

    PubMed  CAS  Google Scholar 

  39. Brennan BJ, Xu ZX, Grippo JF. Evaluation of the absolute bioavailability of pegylated interferon alfa-2a after subcutaneous administration to healthy male volunteers: an open-label, randomized, parallel-group study. Clin Ther. 2012;34(9):1883–91.

    PubMed  CAS  Google Scholar 

  40. Bruno R, Sacchi P, Ciappina V, Zochetti C, Patruno S, Maiocchi L, et al. Viral dynamics and pharmacokinetics of peginterferon alpha-2a and peginterferon alpha-2b in naive patients with chronic hepatitis c: a randomized, controlled study. Antivir Ther. 2004;9(4):491–7.

    PubMed  CAS  Google Scholar 

  41. Keam SJ, Cvetkovic RS. Peginterferon-alpha-2a (40 kD) plus ribavirin: a review of its use in the management of chronic hepatitis C mono-infection. Drugs. 2008;68(9):1273–317.

    PubMed  CAS  Google Scholar 

  42. Perry CM, Jarvis B. Peginterferon-alpha-2a (40 kD): a review of its use in the management of chronic hepatitis C. Drugs. 2001;61(15):2263–88.

    PubMed  CAS  Google Scholar 

  43. Varunok P, Lawitz E, Beavers KL, Matusow G, Leong R, Lambert N, et al. Evaluation of pharmacokinetics, user handling, and tolerability of peginterferon alfa-2a (40 kDa) delivered via a disposable autoinjector device. Patient Prefer Adher. 2011;5:587–99.

    Google Scholar 

  44. Keating GM, Curran MP. Peginterferon-alpha-2a (40kD) plus ribavirin: a review of its use in the management of chronic hepatitis C. Drugs. 2003;63(7):701–30.

    PubMed  CAS  Google Scholar 

  45. Glue P, Fang JW, Rouzier-Panis R, Raffanel C, Sabo R, Gupta SK, et al. Pegylated interferon-alpha2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C Intervention Therapy Group. Clin Pharmacol Ther. 2000;68(5):556–67.

    PubMed  CAS  Google Scholar 

  46. Glue P. The clinical pharmacology of ribavirin. Semin Liver Dis. 1999;19(Suppl 1):17–24.

    PubMed  CAS  Google Scholar 

  47. FDA. Copegus prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021511s026lbl.pdf. Accessed 19 March 2014.

  48. EMA. Rebetol product information. 2013. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000246/WC500048210.pdf. Accessed 19 March 2014.

  49. FDA. Rebetol prescribing information. 2013. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020903s052,021546s008lbl.pdf. Accessed 19 March 2014.

  50. Moss AM, Endres CJ, Ruiz-Garcia A, Choi DS, Unadkat JD. Role of the equilibrative and concentrative nucleoside transporters in the intestinal absorption of the nucleoside drug, ribavirin, in wild-type and Ent1(−/−) mice. Mol Pharm. 2012;9(9):2442–9.

    PubMed Central  PubMed  CAS  Google Scholar 

  51. Endres CJ, Moss AM, Govindarajan R, Choi DS, Unadkat JD. The role of nucleoside transporters in the erythrocyte disposition and oral absorption of ribavirin in the wild-type and equilibrative nucleoside transporter 1−/− mice. J Pharmacol Exp Ther. 2009;331(1):287–96.

    PubMed Central  PubMed  CAS  Google Scholar 

  52. Li L, Koo SH, Limenta LM, Han L, Hashim KB, Quek HH, et al. Effect of dietary purines on the pharmacokinetics of orally administered ribavirin. J Clin Pharmacol. 2009;49(6):661–7.

    PubMed  CAS  Google Scholar 

  53. Jarvis SM, Thorn JA, Glue P. Ribavirin uptake by human erythrocytes and the involvement of nitrobenzylthioinosine-sensitive (es)-nucleoside transporters. Br J Pharmacol. 1998;123(8):1587–92.

    PubMed Central  PubMed  CAS  Google Scholar 

  54. Fukuchi Y, Furihata T, Hashizume M, Iikura M, Chiba K. Characterization of ribavirin uptake systems in human hepatocytes. J Hepatol. 2010;52(4):486–92.

    PubMed  CAS  Google Scholar 

  55. Lertora JJ, Rege AB, Lacour JT, Ferencz N, George WJ, VanDyke RB, et al. Pharmacokinetics and long-term tolerance to ribavirin in asymptomatic patients infected with human immunodeficiency virus. Clin Pharmacol Ther. 1991;50(4):442–9.

    PubMed  CAS  Google Scholar 

  56. Tsubota A, Shimada N, Yoshizawa K, Furihata T, Agata R, Yumoto Y, et al. Contribution of ribavirin transporter gene polymorphism to treatment response in peginterferon plus ribavirin therapy for HCV genotype 1b patients. Liver Int. 2012;32(5):826–36.

    PubMed  CAS  Google Scholar 

  57. Jen JF, Glue P, Gupta S, Zambas D, Hajian G. Population pharmacokinetic and pharmacodynamic analysis of ribavirin in patients with chronic hepatitis C. Ther Drug Monit. 2000;22(5):555–65.

    PubMed  CAS  Google Scholar 

  58. Merck. Boceprevir clinical pharmacology and biopharmaceutics review(s). 2011. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202258orig1s000clinpharmr.pdf. Accessed 11 March 2014.

  59. EMA. Victrelis product information. 2013. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002332/WC500109786.pdf. Accessed 19 March 2014.

  60. FDA. Victrelis prescribing information. 2013. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/202258s009lbl.pdf. Accessed 19 March 2014.

  61. Ghosal A, Yuan Y, Tong W, Su AD, Gu C, Chowdhury SK, et al. Characterization of human liver enzymes involved in the biotransformation of boceprevir, a hepatitis C virus protease inhibitor. Drug Metab Dispos Biol Fate Chem. 2011;39(3):510–21.

    PubMed  CAS  Google Scholar 

  62. Chu X, Cai X, Cui D, Tang C, Ghosal A, Chan G, et al. In vitro assessment of drug–drug interaction potential of boceprevir associated with drug metabolizing enzymes and transporters. Drug Metab Dispos Biol Fate Chem. 2013;41(3):668–81.

    PubMed  CAS  Google Scholar 

  63. EMA. Incivo product information. 2013. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002313/WC500115529.pdf. Accessed 19 March 2014.

  64. FDA. Incivek prescribing information. 2013. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/201917s012lbl.pdf. Accessed 19 March 2014.

  65. Vertex Pharmaceuticals. Telaprevir clinical pharmacology and biopharmaceutics review(s). 2010. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201917Orig1s000ClinPharmR.pdf. Accessed 9 March 2014.

  66. Garg V, Kauffman RS, Beaumont M, van Heeswijk RP. Telaprevir: pharmacokinetics and drug interactions. Antivir Ther. 2012;17(7):1211–21.

    PubMed  CAS  Google Scholar 

  67. Reesink HW, Fanning GC, Farha KA, Weegink C, Van Vliet A, Van ‘t Klooster G, et al. Rapid HCV-RNA decline with once daily TMC435: a phase I study in healthy volunteers and hepatitis C patients. Gastroenterology. 2010;138(3):913–21.

  68. Dickinson L, Khoo S, Back D. Differences in the pharmacokinetics of protease inhibitors between healthy volunteers and HIV-infected persons. Curr Opin HIV AIDS. 2008;3(3):296–305.

    PubMed  Google Scholar 

  69. Janssen. Simeprevir clinical pharmacology and biopharmaceutics review(s). 2013. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf. Accessed 13 March 2014.

  70. Rodriguez-Torres M, Lawitz E, Kowdley KV, Nelson DR, Dejesus E, McHutchison JG, et al. Sofosbuvir (GS-7977) plus peginterferon/ribavirin in treatment-naive patients with HCV genotype 1: a randomized, 28-day, dose-ranging trial. J Hepatol. 2013;58(4):663–8.

    PubMed  CAS  Google Scholar 

  71. Bailon P, Palleroni A, Schaffer CA, Spence CL, Fung WJ, Porter JE, et al. Rational design of a potent, long-lasting form of interferon: a 40 kDa branched polyethylene glycol-conjugated interferon alpha-2a for the treatment of hepatitis C. Bioconjug Chem. 2001;12(2):195–202.

    Google Scholar 

  72. Youngster S, Wang YS, Grace M, Bausch J, Bordens R, Wyss DF. Structure, biology, and therapeutic implications of pegylated interferon alpha-2b. Curr Pharm Des. 2002;8(24):2139–57.

    PubMed  CAS  Google Scholar 

  73. Reddy KR, Wright TL, Pockros PJ, Shiffman M, Everson G, Reindollar R, et al. Efficacy and safety of pegylated (40-kd) interferon alpha-2a compared with interferon alpha-2a in noncirrhotic patients with chronic hepatitis C. Hepatology (Baltimore, Md). 2001;33(2):433–8.

  74. Zeuzem S, Feinman SV, Rasenack J, Heathcote EJ, Lai MY, Gane E, et al. Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med. 2000;343(23):1666–72.

    PubMed  CAS  Google Scholar 

  75. Heathcote EJ, Shiffman ML, Cooksley WG, Dusheiko GM, Lee SS, Balart L, et al. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med. 2000;343(23):1673–80.

    PubMed  CAS  Google Scholar 

  76. Lindsay KL, Trepo C, Heintges T, Shiffman ML, Gordon SC, Hoefs JC, et al. A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C. Hepatology (Baltimore, Md). 2001;34(2):395–3.

  77. Bruno R, Sacchi P, Scagnolari C, Torriani F, Maiocchi L, Patruno S, et al. Pharmacodynamics of peginterferon alpha-2a and peginterferon alpha-2b in interferon-naive patients with chronic hepatitis C: a randomized, controlled study. Aliment Pharmacol Ther. 2007;26(3):369–76.

    PubMed  CAS  Google Scholar 

  78. Shindo M, Hamada K, Morikawa T, Harano Y, Nakajima T, Okuno T. In vivo interferon system assessed by 2’-5’ oligoadenylate synthetase activity in chronic hepatitis C virus patients treated with pegylated interferon and ribavirin. Hepatol Res. 2008;38(12):1213–20.

    PubMed  CAS  Google Scholar 

  79. Francois C, Descamps V, Brochot E, Bernard I, Canva V, Mathurin P, et al. Relationship between the hepatitis C viral load and the serum interferon concentration during the first week of peginterferon-alpha-2b-ribavirin combination therapy. J Med Virol. 2010;82(10):1640–6.

    PubMed  CAS  Google Scholar 

  80. Formann E, Jessner W, Bennett L, Ferenci P. Twice-weekly administration of peginterferon-alpha-2b improves viral kinetics in patients with chronic hepatitis C genotype 1. J Viral Hepat. 2003;10(4):271–6.

    PubMed  CAS  Google Scholar 

  81. Di Bisceglie AM, Ghalib RH, Hamzeh FM, Rustgi VK. Early virologic response after peginterferon alpha-2a plus ribavirin or peginterferon alpha-2b plus ribavirin treatment in patients with chronic hepatitis C. J Viral Hepat. 2007;14(10):721–9.

    PubMed  Google Scholar 

  82. Brochot E, Nguyen-Khac E, Duverlie G. Equal efficacy between the two types of peginterferon on HCV: a matter of relapse? Antivir Res. 2013;98(1):1–3.

    PubMed  CAS  Google Scholar 

  83. McHutchison JG, Lawitz EJ, Shiffman ML, Muir AJ, Galler GW, McCone J, et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361(6):580–93.

    PubMed  CAS  Google Scholar 

  84. Flori N, Funakoshi N, Duny Y, Valats JC, Bismuth M, Christophorou D, et al. Pegylated interferon-alpha2a and ribavirin versus pegylated interferon-alpha2b and ribavirin in chronic hepatitis C: a meta-analysis. Drugs. 2013;73(3):263–77.

    PubMed  CAS  Google Scholar 

  85. Romero-Gomez M, Planas R, Ampuero J, Sola R, Garcia-Samaniego J, Diago M, et al. Meta-analysis: pegylated interferon alpha-2a achieves higher early virological responses than alpha-2b in chronic hepatitis C. Aliment Pharmacol Ther. 2013;37(11):1065–73.

    PubMed  CAS  Google Scholar 

  86. Marcellin P, Forns X, Goeser T, Ferenci P, Nevens F, Carosi G, et al. Telaprevir is effective given every 8 or 12 hours with ribavirin and peginterferon alfa-2a or -2b to patients with chronic hepatitis C. Gastroenterology. 2011;140(2):459–68.

    PubMed  CAS  Google Scholar 

  87. Jacobson IM, Brown RS Jr, Freilich B, Afdhal N, Kwo PY, Santoro J, et al. Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial. Hepatology (Baltimore, Md). 2007;46(4):971–81.

  88. Jacobson IM, Brown RS Jr, McCone J, Black M, Albert C, Dragutsky, et al. Impact of weight-based ribavirin with peginterferon alfa-2b in African Americans with hepatitis C virus genotype 1. Hepatology (Baltimore, Md). 2007;46(4):982–90.

    CAS  Google Scholar 

  89. Snoeck E, Wade JR, Duff F, Lamb M, Jorga K. Predicting sustained virological response and anaemia in chronic hepatitis C patients treated with peginterferon alfa-2a (40KD) plus ribavirin. Br J Clin Pharmacol. 2006;62(6):699–709.

    PubMed Central  PubMed  CAS  Google Scholar 

  90. Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, Marcellin P, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140(5):346–55.

    PubMed  CAS  Google Scholar 

  91. Larrat S, Stanke-Labesque F, Plages A, Zarski JP, Bessard G, Souvignet C. Ribavirin quantification in combination treatment of chronic hepatitis C. Antimicrob Agents Chemother. 2003;47(1):124–9.

    PubMed Central  PubMed  CAS  Google Scholar 

  92. Morello J, Rodriguez-Novoa S, Jimenez-Nacher I, Soriano V. Usefulness of monitoring ribavirin plasma concentrations to improve treatment response in patients with chronic hepatitis C. J Antimicrob Chemother. 2008;62(6):1174–80.

    PubMed  CAS  Google Scholar 

  93. Chan AH, Partovi N, Ensom MH. The utility of therapeutic drug monitoring for ribavirin in patients with chronic hepatitis C—a critical review. Ann Pharmacother. 2009;43(12):2044–63.

    PubMed  CAS  Google Scholar 

  94. Brochot E, Castelain S, Duverlie G, Capron D, Nguyen-Khac E, Francois C. Ribavirin monitoring in chronic hepatitis C therapy: anaemia versus efficacy. Antivir Ther. 2010;15(5):687–95.

    PubMed  CAS  Google Scholar 

  95. Loustaud-Ratti V, Carrier P, Rousseau A, Maynard M, Babany G, Alain S, et al. Pharmacological exposure to ribavirin: a key player in the complex network of factors implicated in virological response and anaemia in hepatitis C treatment. Dig Liver Dis. 2011;43(11):850–5.

    PubMed  CAS  Google Scholar 

  96. Loustaud-Ratti V, Alain S, Rousseau A, Hubert IF, Sauvage FL, Marquet P, et al. Ribavirin exposure after the first dose is predictive of sustained virological response in chronic hepatitis C. Hepatology (Baltimore, Md). 2008;47(5):1453–61.

  97. Arase Y, Ikeda K, Tsubota A, Suzuki F, Suzuki Y, Saitoh S, et al. Significance of serum ribavirin concentration in combination therapy of interferon and ribavirin for chronic hepatitis C. Intervirology. 2005;48(2–3):138–44.

    PubMed  CAS  Google Scholar 

  98. Dominguez S, Ghosn J, Cassard B, Melica G, Poizot-Martin I, Solas C, et al. Erythrocyte and plasma ribavirin concentrations in the assessment of early and sustained virological responses to pegylated interferon-alpha 2a and ribavirin in patients coinfected with hepatitis C virus and HIV. J Antimicrob Chemother. 2012;67(6):1449–52.

    PubMed  CAS  Google Scholar 

  99. Baiocchi L, De Leonardis F, Delle Monache M, Nosotti L, Conti RL, Lenci I, et al. Plasma/erythrocyte ribavirin ×100 ratio as an indicator of sustained virological response in HCV genotype 1 patients with early virological response. Antivir Ther. 2010;15(4):633–9.

    Google Scholar 

  100. De Franceschi L, Fattovich G, Turrini F, Ayi K, Brugnara C, Manzato F, et al. Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: role of membrane oxidative damage. Hepatology (Baltimore, Md). 200031(4):997–4.

  101. Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet. 1998;352(9138):1426–32.

    PubMed  CAS  Google Scholar 

  102. Lindahl K, Schvarcz R, Bruchfeld A, Stahle L. Evidence that plasma concentration rather than dose per kilogram body weight predicts ribavirin-induced anaemia. J Viral Hepat. 2004;11(1):84–7.

    PubMed  CAS  Google Scholar 

  103. Smee DF, Matthews TR. Metabolism of ribavirin in respiratory syncytial virus-infected and uninfected cells. Antimicrob Agents Chemother. 1986;30(1):117–21.

    PubMed Central  PubMed  CAS  Google Scholar 

  104. Fellay J, Thompson AJ, Ge D, Gumbs CE, Urban TJ, Shianna KV, et al. ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C. Nature. 2010;464(7287):405–8.

    PubMed  CAS  Google Scholar 

  105. Hofer H, Donnerer J, Sator K, Staufer K, Scherzer TM, Dejaco C, et al. Seminal fluid ribavirin level and functional semen parameters in patients with chronic hepatitis C on antiviral combination therapy. J Hepatol. 2010;52(6):812–6.

    PubMed  CAS  Google Scholar 

  106. Lindahl K, Stahle L, Bruchfeld A, Schvarcz R. High-dose ribavirin in combination with standard dose peginterferon for treatment of patients with chronic hepatitis C. Hepatology (Baltimore, Md). 2005;41(2):275–9.

  107. Trepo C. RIBAJUSTE clinical trial investigating the efficacy and safety of dose adaptation of ribavirin. 2013. http://clinicaltrials.gov/ct2/show/NCT00485342?term=ribajuste&rank=1. Accessed 20 Dec 2013.

  108. EMA. Victrelis: EPAR public assessment report. 2011. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002332/WC500109789.pdf. Accessed 10 December 2013.

  109. Reesink HW, Zeuzem S, Weegink CJ, Forestier N, van Vliet A, van de Wetering de Rooij J, et al. Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study. Gastroenterology. 2006131(4):997–2.

  110. EMA. Incivo: EPAR public assessment report. 2011. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002313/WC500115532.pdf. Accessed 10 Dec 2013.

  111. Furusyo N, Ogawa E, Murata M, Toyoda K, Ohnishi H, Eiraku K, et al. Therapeutic drug monitoring of telaprevir in chronic hepatitis C patients receiving telaprevir-based triple therapy is useful for predicting virological response. J Antimicrob Chemother. 2014;69(2):483–90.

    PubMed  CAS  Google Scholar 

  112. Sciences G. Sofosbuvir clinical pharmacology and biopharmaceutics review(s). 2013. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204671Orig1s000ClinPharmR.pdf. Accessed 15 Mar 2014.

  113. Kunze A, Huwyler J, Camenisch G, Gutmann H. Interaction of the antiviral drug telaprevir with renal and hepatic drug transporters. Biochem Pharmacol. 2012;84(8):1096–102.

    PubMed  CAS  Google Scholar 

  114. Fujita Y, Noguchi K, Suzuki T, Katayama K, Sugimoto Y. Biochemical interaction of anti-HCV telaprevir with the ABC transporters P-glycoprotein and breast cancer resistance protein. BMC Res Notes. 2013;6:445.

    PubMed  Google Scholar 

  115. Kiser JJ, Burton JR, Anderson PL, Everson GT. Review and management of drug interactions with boceprevir and telaprevir. Hepatology (Baltimore, Md). 2012;55(5):1620–8.

  116. Burger D, Back D, Buggisch P, Buti M, Craxi A, Foster G, et al. Clinical management of drug–drug interactions in HCV therapy: Challenges and solutions. J Hepatol. 2013;58(4):792–800.

    PubMed  CAS  Google Scholar 

  117. Back D, Else L. The importance of drug–drug interactions in the DAA era. Dig Liver Dis. 2013;30(45 Suppl 5):S343–8.

    Google Scholar 

  118. Maasoumy B, Port K, Calle Serrano B, Markova AA, Sollik L, Manns MP, et al. The clinical significance of drug–drug interactions in the era of direct-acting anti-viral agents against chronic hepatitis C. Aliment Pharmacol Ther. 2013;38(11–12):1365–72.

    Google Scholar 

  119. Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol. 2008;64(12):1147–61.

    PubMed  CAS  Google Scholar 

  120. Glue P, Schenker S, Gupta S, Clement RP, Zambas D, Salfi M. The single dose pharmacokinetics of ribavirin in subjects with chronic liver disease. Br J Clin Pharmacol. 2000;49(5):417–21.

    PubMed Central  PubMed  CAS  Google Scholar 

  121. Treitel M, Marbury T, Preston RA, Triantafyllou I, Feely W, O’Mara E, et al. Single-dose pharmacokinetics of boceprevir in subjects with impaired hepatic or renal function. Clin Pharmacokinet. 2012;51(9):619–28.

    PubMed  CAS  Google Scholar 

  122. Hezode C, Fontaine H, Dorival C, Larrey D, Zoulim F, Canva V, et al. Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) - NCT01514890. J Hepatol. 2013;59(3):434–41.

    PubMed  Google Scholar 

  123. Gupta SK, Swan SK, Marbury T, Smith W, Schwartz S, Kolz K, et al. Multiple-dose pharmacokinetics of peginterferon alfa-2b in patients with renal insufficiency. Br J Clin Pharmacol. 2007;64(6):726–32.

    PubMed Central  PubMed  CAS  Google Scholar 

  124. Barril G, Quiroga JA, Sanz P, Rodriguez-Salvanes F, Selgas R, Carreno V. Pegylated interferon-alpha2a kinetics during experimental haemodialysis: impact of permeability and pore size of dialysers. Aliment Pharmacol Ther. 2004;20(1):37–44.

    PubMed  CAS  Google Scholar 

  125. Gupta SK, Kantesaria B, Glue P. Pharmacokinetics, safety, and tolerability of ribavirin in hemodialysis-dependent patients. Eur J Clin Pharmacol. 2012;68(4):415–8.

    PubMed  CAS  Google Scholar 

  126. Bruchfeld A, Lindahl K, Reichard O, Carlsson T, Schvarcz R. Pegylated interferon and ribavirin treatment for hepatitis C in haemodialysis patients. J Viral Hepat. 2006;13(5):316–21.

    PubMed  CAS  Google Scholar 

  127. Tseng PL, Chen TC, Chien YS, Hung CH, Yen YH, Chang KC, et al. Efficacy and safety of pegylated interferon alfa-2b and ribavirin combination therapy versus pegylated interferon monotherapy in hemodialysis patients: a comparison of 2 sequentially treated cohorts. Am J Kidney Dis. 2013;62(4):789–95.

    PubMed  CAS  Google Scholar 

  128. Dumortier J, Guillaud O, Gagnieu MC, Janbon B, Juillard L, Morelon E, et al. Anti-viral triple therapy with telaprevir in haemodialysed HCV patients: is it feasible? J Clin Virol. 2013;56(2):146–9.

    PubMed  CAS  Google Scholar 

  129. Egger M, May M, Chene G, Phillips AN, Ledergerber B, Dabis F, et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet. 2002;360(9327):119–29.

    PubMed  Google Scholar 

  130. Lacombe K, Rockstroh J. HIV and viral hepatitis coinfections: advances and challenges. Gut. 2012;61(Suppl 1):i47–58.

    PubMed  CAS  Google Scholar 

  131. Sherman KE, Rouster SD, Chung RT, Rajicic N. Hepatitis C Virus prevalence among patients infected with Human Immunodeficiency Virus: a cross-sectional analysis of the US adult AIDS Clinical Trials Group. Clin Infect Dis. 2002;34(6):831–7.

    PubMed  Google Scholar 

  132. Weber R, Ruppik M, Rickenbach M, Spoerri A, Furrer H, Battegay M, et al. Decreasing mortality and changing patterns of causes of death in the Swiss HIV Cohort Study. HIV Med. 2013;14(4):195–207.

    PubMed  CAS  Google Scholar 

  133. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, Lissen E, Gonzalez-Garcia J, Lazzarin A, et al. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med. 2004;351(5):438–50.

    PubMed  CAS  Google Scholar 

  134. Rodriguez-Torres M, Slim J, Bhatti L, Sterling R, Sulkowski M, Hassanein T, et al. Peginterferon alfa-2a plus ribavirin for HIV-HCV genotype 1 coinfected patients: a randomized international trial. HIV Clin Trials. 2012;13(3):142–52.

    PubMed  CAS  Google Scholar 

  135. Sulkowski M, Pol S, Mallolas J, Fainboim H, Cooper C, Slim J, et al. Boceprevir versus placebo with pegylated interferon alfa-2b and ribavirin for treatment of hepatitis C virus genotype 1 in patients with HIV: a randomised, double-blind, controlled phase 2 trial. Lancet Infect Dis. 2013;13(7):597–605.

    PubMed  CAS  Google Scholar 

  136. Sulkowski MS, Sherman KE, Dieterich DT, Bsharat M, Mahnke L, Rockstroh JK, et al. Combination therapy with telaprevir for chronic hepatitis C virus genotype 1 infection in patients with HIV: a randomized trial. Ann Intern Med. 2013;159(20):86–96

    Google Scholar 

  137. Chastain CA, Naggie S. Treatment of genotype 1 HCV infection in the HIV coinfected patient in 2014. Curr HIV/AIDS Rep. 2013;10(4):408–19.

    PubMed  Google Scholar 

  138. Luetkemeyer AF, Havlir DV, Currier JS. CROI 2013: complications of HIV disease, viral hepatitis, and antiretroviral therapy. Top Antivir Med. 2013;21(2):62–74.

    PubMed  Google Scholar 

  139. Karageorgopoulos DE, El-Sherif O, Bhagani S, Khoo SH. Drug interactions between antiretrovirals and new or emerging direct-acting antivirals in HIV/hepatitis C virus coinfection. Curr Opin Infect Dis. 2014;27(1):36–45.

    PubMed  CAS  Google Scholar 

  140. Gonzalez-Peralta RP, Kelly DA, Haber B, Molleston J, Murray KF, Jonas MM, et al. Interferon alfa-2b in combination with ribavirin for the treatment of chronic hepatitis C in children: efficacy, safety, and pharmacokinetics. Hepatology (Baltimore, Md). 2005;42(5):1010–8.

  141. Schwarz KB, Mohan P, Narkewicz MR, Molleston JP, Nash SR, Hu S, et al. Safety, efficacy and pharmacokinetics of peginterferon alpha2a (40 kd) in children with chronic hepatitis C. J Pediatr Gastroenterol Nutr. 2006;43(4):499–505.

    PubMed  CAS  Google Scholar 

  142. Xu C, Gupta S, Krishna G, Cutler D, Wirth S, Galoppo C, et al. Population pharmacokinetics of peginterferon alfa-2b in pediatric patients with chronic hepatitis C. Eur J Clin Pharmacol. 2013;69(12):2045–54.

    PubMed  CAS  Google Scholar 

  143. Schwarz KB, Gonzalez-Peralta RP, Murray KF, Molleston JP, Haber BA, Jonas MM, et al. The combination of ribavirin and peginterferon is superior to peginterferon and placebo for children and adolescents with chronic hepatitis C. Gastroenterology. 2011;140(2):450–8 e1.

    Google Scholar 

  144. Wirth S, Ribes-Koninckx C, Calzado MA, Bortolotti F, Zancan L, Jara P, et al. High sustained virologic response rates in children with chronic hepatitis C receiving peginterferon alfa-2b plus ribavirin. J Hepatol. 2010;52(4):501–7.

    PubMed  CAS  Google Scholar 

  145. Liang TJ, Ghany MG. Current and future therapies for hepatitis C virus infection. N Engl J Med. 2013;368(20):1907–17.

    PubMed Central  PubMed  CAS  Google Scholar 

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Acknowledgments

No sources of funding were used in the preparation of this review. Clara T. M. M. de Kanter and Joost P. H. Drenth have no conflicts of interest that are directly relevant to the content of this review. Joop E. Arends received consulting fees or payment for lectures from Janssen, BMS, Abbvie, Roche, MSD and Gilead. David M. Burger received research grants, consulting fees or payment for lectures from Merck, Janssen and Roche. Marc van der Valk received research grants or consulting fees from Janssen-Cilag, Abbvie, Gilead, BMS and MSD. Robert J. de Knegt received research grants, consulting fees or payment for lectures form Roche, BMS, Merck, Gilead, Abbvie and from Janssen-Cilag. Henk W. Reesink received research support or consulting fees from Abbvie, Astex, BMS, Boehringer Ingelheim, Gilead, GlaxoSmithCline, Janssen-Cilag, Merck, PRA-International, Roche, Santaris, Tibotec, R-Pharm and Regulus. However, these conflicts of interest did not influence the preparation of this review.

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de Kanter, C.T.M.M., Drenth, J.P.H., Arends, J.E. et al. Viral Hepatitis C Therapy: Pharmacokinetic and Pharmacodynamic Considerations. Clin Pharmacokinet 53, 409–427 (2014). https://doi.org/10.1007/s40262-014-0142-5

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