Skip to main content
SpringerLink
Log in

Pharmacokinetics and Tolerability of Anti-Hepatitis C Virus Treatment with Ombitasvir, Paritaprevir, Ritonavir, with or Without Dasabuvir, in Subjects with Renal Impairment

  • Original Research Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background

The direct-acting antiviral agent (DAA) combination of ombitasvir and paritaprevir (administered with ritonavir) with (3D regimen) or without (2D regimen) dasabuvir has shown very high efficacy rates in the treatment of chronic hepatitis C virus (HCV) infection. Renal impairment, a common comorbidity in patients with chronic HCV infection, can influence the pharmacokinetics of antiviral agents and hence their efficacy and safety profiles.

Objective

The aim of this study was to evaluate the influence of renal impairment on the pharmacokinetics and tolerability of the 3D and 2D regimens.

Methods

Overall, 24 subjects, six in each of four renal function groups (normal, mild, moderate, and severe), received a single dose of the 3D and 2D regimens in separate dosing periods. Plasma and urine were analyzed to assess the effect of renal impairment on drug exposure.

Results

DAA exposures changed by up to 21, 37, and 50 % in subjects with mild, moderate, and severe renal impairment, respectively, versus subjects with normal renal function. Ritonavir exposure increased with the degree of renal impairment (maximum 114 %). The half-lives of DAAs and ritonavir in subjects with renal impairment were generally comparable with those in healthy subjects. No safety or tolerability concerns arose in this study.

Conclusion

The 3D and 2D regimens do not require dose adjustment for patients with HCV infection and concomitant renal impairment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Finelli L, Miller JT, Tokars JI, Alter MJ, Arduino MJ. National surveillance of dialysis-associated diseases in the United States, 2002. Semin Dial. 2005;18:52–61.

    Article  PubMed  Google Scholar 

  2. Tsui JI, Vittinghoff E, Shlipak MG, Bertenthal D, Inadomi J, Rodriguez RA, et al. Association of hepatitis C seropositivity with increased risk for developing end-stage renal disease. Arch Intern Med. 2007;167:1271–6.

    Article  PubMed  Google Scholar 

  3. Butt AA, Wang X, Fried LF. HCV infection and the incidence of CKD. Am J Kidney Dis. 2011;57:396–402.

    Article  PubMed  Google Scholar 

  4. Lucas GM, Jing Y, Sulkowski M, Abraham AG, Estrella MM, Atta MG, et al. Hepatitis C viremia and the risk of chronic kidney disease in HIV-infected individuals. J Infect Dis. 2013;208:1240–9.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Gilead Sciences Inc. Harvoni (ledipasvir and sofobuvir) tablets, for oral use. Approved prescribing information. Updated Mar 2015. Available at: http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/harvoni/harvoni_pi.pdf. Accessed 2 Nov 2015.

  6. Genentech USA Inc. Pegasys (peginterferon alfa-2a) injection, for subcutaneous use. Approved prescribing information. Updated Mar 2015. Available at: http://www.gene.com/download/pdf/pegasys_prescribing.pdf. Accessed 2 Nov 2015.

  7. Krishnan P, Beyer J, Mistry N, Koev G, Reisch T, DeGoey D, et al. In vitro and in vivo antiviral activity and resistance profile of ombitasvir, an inhibitor of hepatitis C virus NS5A. Antimicrob Agents Chemother. 2015;59:979–87.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Pilot-Matias T, Tripathi R, Cohen D, Gaultier I, Dekhtyar T, Lu L, et al. In vitro and in vivo antiviral activity and resistance profile of the hepatitis C virus NS3/4A protease inhibitor ABT-450. Antimicrob Agents Chemother. 2015;59:988–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Andreone P, Colombo MG, Enejosa JV, Koksal I, Ferenci P, Maieron A, et al. ABT-450, ritonavir, ombitasvir, and dasabuvir achieves 97 % and 100 % sustained virologic response with or without ribavirin in treatment-experienced patients with HCV genotype 1b infection. Gastroenterology. 2014;147(359–65):e1.

    Google Scholar 

  10. Ferenci P, Bernstein D, Lalezari J, Cohen D, Luo Y, Cooper C, et al. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med. 2014;370:1983–92.

    Article  PubMed  Google Scholar 

  11. Poordad F, Hezode C, Trinh R, Kowdley KV, Zeuzem S, Agarwal K, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med. 2014;370:1973–82.

    Article  PubMed  Google Scholar 

  12. Feld JJ, Kowdley KV, Coakley E, Sigal S, Nelson DR, Crawford D, et al. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014;370:1594–603.

    Article  CAS  PubMed  Google Scholar 

  13. Zeuzem S, Jacobson IM, Baykal T, Marinho RT, Poordad F, Bourliere M, et al. Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014;370:1604–14.

    Article  CAS  PubMed  Google Scholar 

  14. AbbVie Ltd. Viekirax (ombitasvir, paritaprevir, ritonavir) tablets, for oral use. Summary of product characteristics. Updated 24 Sep 2015. Available at: https://www.medicines.org.uk/emc/medicine/29784. Accessed 2 Nov 2015.

  15. Hezode C, Asselah T, Reddy KR, Hassanein T, Berenguer M, Fleischer-Stepniewska K, et al. Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial. Lancet. 2015;385:2502–9.

    Article  CAS  PubMed  Google Scholar 

  16. Chayama K, Notsumata K, Kurosaki M, Sato K, Rodrigues L Jr, Setze C, et al. Randomized trial of interferon- and ribavirin-free ombitasvir/paritaprevir/ritonavir in treatment-experienced hepatitis C virus-infected patients. Hepatology. 2015;61:1523–32.

    Article  CAS  PubMed  Google Scholar 

  17. Kumada H, Chayama K, Rodrigues L Jr, Suzuki F, Ikeda K, Toyoda H, et al. Randomized phase 3 trial of ombitasvir/paritaprevir/ritonavir for hepatitis C virus genotype 1b-infected Japanese patients with or without cirrhosis. Hepatology. 2015;62:1037–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. AbbVie Inc. Viekira Pak (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets), co-packaged for oral use. Approved prescribing information. Updated Oct 2015. Available at: http://www.rxabbvie.com/pdf/viekirapak_pi.pdf. Accessed 2 Nov 2015.

  19. US Department of Health and Human Services. Guidance for industry: pharmacokinetics in patients with impaired renal function—study design, data analysis, and impact on dosing and labeling, 2010. Available at: http://www.fda.gov/downloads/Drugs/Guidances/UCM204959.pdf. Accessed 2 Nov 2015.

  20. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41.

    Article  CAS  PubMed  Google Scholar 

  21. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130:461–70.

  22. Polepally AR, Dutta S, Hu B, Podsadecki TJ, Awni WM, Menon RM. Drug-drug interaction of omeprazole with the HCV direct-acting antiviral agents paritaprevir/ritonavir and ombitasvir with and without dasabuvir. Clin Pharm Drug Dev. 2016;5(4):269–77.

    Article  CAS  Google Scholar 

  23. Committee for Medicinal Products for Human Use (CHMP). Note for guidance on the evaluation of the pharmacokinetics of medicinal products in patients with impaired renal function. London: European Medicines Agency; 2004.

  24. Hill A, van der Lugt J, Sawyer W, Boffito M. How much ritonavir is needed to boost protease inhibitors? Systematic review of 17 dose-ranging pharmacokinetic trials. AIDS. 2009;23:2237–45.

    Article  CAS  PubMed  Google Scholar 

  25. Poordad F, Lawitz E, Kowdley KV, Cohen DE, Podsadecki T, Siggelkow S, et al. Exploratory study of oral combination antiviral therapy for hepatitis C. N Engl J Med. 2013;368:45–53.

    Article  CAS  PubMed  Google Scholar 

  26. Sullivan GJ, Rodrigues-Torres M, Lawitz E, Poordad F, Kapoor M, Campbell A, et al. ABT-267 combined with pegylated interferon alpha-2a/ribavirin in genotype 1 (GT1) HCV-infected treatment-naive subjects: 12 week antiviral and safety analysis. J Hepatol. 2012;56:S480.

    Article  Google Scholar 

  27. Merck & Co. Inc. Victrelis (boceprevir) capsules, for oral use. Approved prescribing information. Updated Aug 2015. Available at: http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf. Accessed 2 Nov 2015.

  28. Vertex Pharmaceuticals Inc. Incivek (telaprevir) tablets, for oral use. Approved prescribing information. Updated Oct 2013. Available at: http://pi.vrtx.com/files/uspi_telaprevir.pdf. Accessed 2 Nov 2015.

  29. de Kanter CT, Drenth JP, Arends JE, Reesink HW, van der Valk M, de Knegt RJ, et al. Viral hepatitis C therapy: pharmacokinetic and pharmacodynamic considerations. Clin Pharmacokinet. 2014;53:409–27.

    Article  PubMed  Google Scholar 

  30. Thompson JR. Emerging therapeutic options for the management of hepatitis C infection. World J Gastroenterol. 2014;20:7079–88.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Cortez KJ, Kottilil S. Beyond interferon: rationale and prospects for newer treatment paradigms for chronic hepatitis C. Ther Adv Chronic Dis. 2015;6:4–14.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Bristol-Myers-Squibb. Daklinza (daclatasvir) tablets, for oral use. Summary of product characteristics. Updated 24 Sep 2015. Available at: https://www.medicines.org.uk/emc/medicine/29129. Accessed 2 Nov 2015.

  33. Garimella T, Wang R, Luo WL, Hwang C, Sherman D, Kandoussi H, et al. Single-dose pharmacokinetics and safety of daclatasvir in subjects with renal function impairment. Antivir Ther. 2015;20:535–43.

    Article  CAS  PubMed  Google Scholar 

  34. Janssen Products. Olysio (simeprevir) capsules, for oral use. Approved prescribing information. Updated Oct 2015. Available at: http://www.olysio.com/shared/product/olysio/prescribing-information.pdf. Accessed 2 Nov 2015.

Download references

Acknowledgments

The authors thank the study investigators, subjects, clinical sites, AbbVie personnel, including James Jankowski, Weihan Zhao, and Jeffrey Arnold, for their contribution to various aspects of the studies; Peter Probst of PRA Health Sciences working under contract with AbbVie for contributions at the time of study; and Kelly Cameron, PhD, and Crystal Murcia, PhD, of The JB Ashtin Group, Inc., for assistance in preparing this manuscript for publication. AbbVie provided funding to The JB Ashtin Group, Inc. for assisting in the preparation of this manuscript. All authors critically reviewed the manuscript, approved the final version for submission, and accept overall responsibility for the accuracy of the data, its analysis, and this report.

Author information

Authors and Affiliations

  1. Clinical Pharmacology and Pharmacometrics, AbbVie Inc., Dept. R4PK, Bldg. AP-31-3, 1 North Waukegan Rd, North Chicago, IL, 60064, USA

    Amit Khatri, Sandeep Dutta, Walid M. Awni & Rajeev M. Menon

  2. Clinical Research, Orlando Clinical Research Center, Orlando, FL, USA

    Thomas C. Marbury

  3. Division of Clinical Pharmacology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL, USA

    Richard A. Preston

  4. Antiviral Global Project Team, AbbVie Inc., North Chicago, IL, USA

    Lino Rodrigues Jr

  5. Biometrics, AbbVie Inc., North Chicago, IL, USA

    Haoyu Wang

Authors
  1. Amit Khatri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sandeep Dutta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas C. Marbury
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Richard A. Preston
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lino Rodrigues Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Haoyu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Walid M. Awni
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rajeev M. Menon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Amit Khatri.

Ethics declarations

Funding

This study was supported by AbbVie Inc. AbbVie contributed to the study design, research, and interpretation of data, writing, reviewing, and approving the manuscript for publication, and provided funding to The JB Ashtin Group, Inc. for assisting in preparation of this manuscript.

Conflict of interest

Amit Khatri, Sandeep Dutta, Lino Rodrigues Jr., Haoyu Wang, Walid M. Awni, and Rajeev M. Menon are employees of AbbVie and may hold AbbVie stocks or options. Thomas C. Marbury is an employee of Orlando Clinical Research Center, Orlando, FL, USA, and Richard A. Preston is faculty at the Miller School of Medicine, University of Miami, Miami, FL, USA.

Ethical approval

This study was conducted in accordance with the Good Clinical Practice Guideline as defined by the International Conference on Harmonisation, the Declaration of Helsinki, and all applicable federal and local regulations. The study was approved by independent institutional review boards.

Informed consent

Written informed consent was obtained from each subject before any study-related procedures were performed.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Khatri, A., Dutta, S., Marbury, T.C. et al. Pharmacokinetics and Tolerability of Anti-Hepatitis C Virus Treatment with Ombitasvir, Paritaprevir, Ritonavir, with or Without Dasabuvir, in Subjects with Renal Impairment. Clin Pharmacokinet 56, 153–163 (2017). https://doi.org/10.1007/s40262-016-0429-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-016-0429-9

Keywords

Search

Navigation