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Effects of chronic kidney disease stage 4, end-stage renal disease, or dialysis on the plasma concentrations of ombitasvir, paritaprevir, ritonavir, and dasabuvir in patients with chronic HCV infection: pharmacokinetic analysis of the phase 3 RUBY-I and RUBY-II trials

  • Diana L. Shuster
  • Rajeev M. Menon
  • Bifeng Ding
  • Amit Khatri
  • Hong Li
  • Eric Cohen
  • Melissa Jewett
  • Daniel E. Cohen
  • Jiuhong Zha
Pharmacokinetics and Disposition
  • 41 Downloads

Abstract

Purpose

To characterize the pharmacokinetics of ombitasvir, paritaprevir, ritonavir, dasabuvir, and ribavirin in hepatitis C virus (HCV)-infected patients with chronic kidney disease stage 4 (CKD4) or end-stage renal disease (ESRD), including those on dialysis, in the open-label phase 3 RUBY-I and RUBY-II studies.

Methods

Patients (n = 18 CKD4, n = 68 ESRD) received ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily ± dasabuvir 250 mg twice daily ± ribavirin 200 mg once daily for 12 or 24 weeks. Intensive pharmacokinetic samples were collected from ten patients; sparse samples were collected from all patients. Arterial and venous samples were collected from three patients during hemodialysis. Area under the plasma concentration-time curve (AUC) was estimated using noncompartmental analyses for intensive data, and steady-state trough concentrations (Ctrough) were obtained from the sparse data. Pharmacokinetic results from RUBY-I and RUBY-II were compared empirically to historical data.

Results

The AUC values of ombitasvir, paritaprevir, ritonavir, and dasabuvir were comparable between CKD4 and ESRD patients and were within the range of values observed in historical studies; dialysis had no effect on drug exposures. Ribavirin was extracted during hemodialysis but had similar exposures on dialysis and non-dialysis days. Individual steady-state Ctrough values for each drug overlapped between CKD4 and ESRD patients, and values in both groups were similar to historical values.

Conclusion

Plasma concentrations of ombitasvir, paritaprevir, ritonavir, and dasabuvir were not altered by renal impairment or dialysis, suggesting these agents can be administered to HCV-infected CKD4 or ESRD patients, including those on dialysis, without dose adjustment.

Trial registration

Clinicaltrials.gov identifiers: NCT02207088 (RUBY-I) and NCT02487199 (RUBY-II)

Keywords

Hepatitis C virus End-stage renal disease Chronic kidney disease Renal impairment Ombitasvir/paritaprevir/ritonavir Dasabuvir 

Notes

Acknowledgements

The authors thank the clinical sites, investigators, and AbbVie Drug Analysis. The authors thank Sonja Kemmis Causemaker, an employee of AbbVie, for her medical writing support.

Authors’ contributions

Diana L. Shuster, Rajeev M. Menon, Bifeng Ding, Amit Khatri, Hong Li, Eric Cohen, Melissa Jewett, Daniel E. Cohen, and Jiuhong Zha contributed to the study design and analysis and interpretation of the data as well as the drafting and revising of the manuscript.

Funding

AbbVie provided financial support for the studies and participated in the design, study conduct, analysis, and interpretation of data as well as the writing, review, and approval of the manuscript.

Compliance with ethical standards

Conflict of interest

DLS, RMM, BD, AK, HL, EC, DEC, and JZ are current or former employees of AbbVie and may hold AbbVie stock and/or stock options. MJ is a contractor of AbbVie, employed by InVentiv Health.

Ethics approval

The studies were conducted in accordance with International Council for Harmonization Good Clinical Practice guidelines and ethical principles that have their origin in the Declaration of Helsinki. The study protocols were approved by the independent ethics committees/institutional review boards.

Informed consent

Informed consent was obtained from all individual participants included in the studies.

Supplementary material

228_2018_2566_MOESM1_ESM.docx (24 kb)
ESM 1 (DOCX 24 kb)

References

  1. 1.
    Azmi AN, Tan SS, Mohamed R (2015) Hepatitis C and kidney disease: an overview and approach to management. World J Hepatol 7:78–92CrossRefGoogle Scholar
  2. 2.
    Tsui JI, Vittinghoff E, Shlipak MG, Bertenthal D, Inadomi J, Rodriguez RA, O'Hare AM (2007) Association of hepatitis C seropositivity with increased risk for developing end-stage renal disease. Arch Intern Med 167:1271–1276CrossRefGoogle Scholar
  3. 3.
    Butt AA, Wang X, Fried LF (2011) HCV infection and the incidence of CKD. Am J Kidney Dis 57:396–402CrossRefGoogle Scholar
  4. 4.
    Lucas GM, Jing Y, Sulkowski M, Abraham AG, Estrella MM, Atta MG, Fine DM, Klein MB, Silverberg MJ, Gill MJ, Moore RD, Gebo KA, Sterling TR, Butt AA, for the NA-ACCORD of the IeDEA (2013) Hepatitis C viremia and the risk of chronic kidney disease in HIV-infected individuals. J Infect Dis 208:1240–1249CrossRefGoogle Scholar
  5. 5.
    Chen Y-C, Chiou W-Y, Hung S-K, Su Y-C, Hwang S-J (2013) Hepatitis C virus itself is a causal risk factor for chronic kidney disease beyond traditional risk factors: a 6-year nationwide cohort study across Taiwan. BMC Nephrol 14:187CrossRefGoogle Scholar
  6. 6.
    Park H, Chen C, Wang W, Henry L, Cook RL, Nelson DR (2018) Chronic hepatitis C increases the risk of chronic kidney disease (CKD) while effective HCV treatment decreases the incidence of CKD. Hepatology 67:492–504CrossRefGoogle Scholar
  7. 7.
    Fabrizi F, Verdesca S, Messa P, Martin P (2015) Hepatitis C virus infection increases the risk of developing chronic kidney disease: a systematic review and meta-analysis. Dig Dis Sci 60:3801–3813CrossRefGoogle Scholar
  8. 8.
    Molnar MZ, Alhourani HM, Wall BM, Lu JL, Streja E, Kalantar-Zadeh K, Kovesdy CP (2015) Association of hepatitis C viral infection with incidence and progression of chronic kidney disease in a large cohort of US veterans. Hepatology 61:1495–1502CrossRefGoogle Scholar
  9. 9.
    Lee JJ, Lin MY, Chang JS, Hung CC, Chang JM, Chen HC, Yu ML, Hwang SJ (2014) Hepatitis C virus infection increases risk of developing end-stage renal disease using competing risk analysis. PLoS One 9:e100790CrossRefGoogle Scholar
  10. 10.
    Fabrizi F, Dixit V, Messa P (2012) Impact of hepatitis C on survival in dialysis patients: a link with cardiovascular mortality? J Viral Hepat 19:601–607CrossRefGoogle Scholar
  11. 11.
    Heo NY, Mannalithara A, Kim D, Udompap P, Tan JC, Kim WR (2018) Long-term patient and graft survival of kidney transplant recipients with hepatitis C virus infection in the United States. Transplantation 102:454–460PubMedGoogle Scholar
  12. 12.
    Kirby BJ, Symonds WT, Kearney BP, Mathias AA (2015) Pharmacokinetic, pharmacodynamic, and drug-interaction profile of the hepatitis C virus NS5B polymerase inhibitor sofosbuvir. Clin Pharmacokinet 54:677–690CrossRefGoogle Scholar
  13. 13.
    AASLD-IDSA (2017) Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus (unique populations/renal impairment). American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA) [online] [accessed on 01 Oct 2018] Available at: https://www.hcvguidelines.org/unique-populations/renal-impairment
  14. 14.
    Viekirax (ombitasvir, paritaprevir, and ritonavir) (2018) Summary of product characteristics. AbbVie Deutschland GmbH & Co. KG, GermanyGoogle Scholar
  15. 15.
    Exviera (dasabuvir) (2018) Summary of product characteristics. AbbVie Deutschland GmbH & Co. KG, GermanyGoogle Scholar
  16. 16.
    Viekira Pak (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets) (2018) [US package insert]. North Chicago, IL: AbbVie Inc.Google Scholar
  17. 17.
    Viekira XR (dasabuvir, ombitasvir, paritaprevir, ritonavir) (2018) [US package insert]. North Chicago, IL: AbbVie Inc.Google Scholar
  18. 18.
    Technivie (ombitasvir, paritaprevir, and ritonavir) (2018) [US Package Insert]. North Chicago, IL: AbbVie Inc.Google Scholar
  19. 19.
    Shen J, Serby M, Reed A, Lee AJ, Menon R, Zhang X, Marsh K, Wan X, Kavetskaia O, Fischer V (2016) Metabolism and disposition of hepatitis C polymerase inhibitor dasabuvir in humans. Drug Metab Dispos 44:1139–1147CrossRefGoogle Scholar
  20. 20.
    Shen J, Serby M, Surber B, Lee AJ, Ma J, Badri P, Menon R, Kavetskaia O, de Morais SM, Sydor J, Fischer V (2016) Metabolism and disposition of pan-genotypic inhibitor of hepatitis C virus NS5A ombitasvir in humans. Drug Metab Dispos 44:1148–1157CrossRefGoogle Scholar
  21. 21.
    Shen J, Serby M, Reed A, Lee AJ, Zhang X, Marsh K, Khatri A, Menon R, Kavetskaia O, Fischer V (2016) Metabolism and disposition of the hepatitis C protease inhibitor paritaprevir in humans. Drug Metab Dispos 44:1164–1173CrossRefGoogle Scholar
  22. 22.
    Khatri A, Dutta S, Marbury T, Preston RA, Rodrigues L Jr, Wang H et al (2017) 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.  https://doi.org/10.1007/s40262-016-0429-9:153-163 CrossRefPubMedGoogle Scholar
  23. 23.
    Polepally AR, Badri PS, Eckert D, Mensing S, Menon RM (2016) Effects of mild and moderate renal impairment on ombitasvir, paritaprevir, ritonavir, dasabuvir, and ribavirin pharmacokinetics in patients with chronic HCV infection. Eur J Drug Metab Pharmacokinet 42:333–339CrossRefGoogle Scholar
  24. 24.
    Pockros PJ, Reddy KR, Mantry PS, Cohen E, Bennett M, Sulkowski MS, Bernstein DE, Cohen DE, Shulman NS, Wang D, Khatri A, Abunimeh M, Podsadecki T, Lawitz E (2016) Efficacy of direct-acting antiviral combination for patients with hepatitis C virus genotype 1 infection and severe renal impairment or end-stage renal disease. Gastroenterology 150:1590–1598CrossRefGoogle Scholar
  25. 25.
    Vierling JM, Lawitz E, Reddy KR, Cohen E, Kemmer N, Morelli G et al (2016) RUBY-I: safety and efficacy of ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin in adults with genotype 1 chronic hepatitis C virus (HCV) infection with severe renal impairment or end-stage renal disease. American Association for the Study of Liver Diseases (AASLD); 11–15 November 2016; BostonGoogle Scholar
  26. 26.
    Gane E, Sola R, Cohen E, Roberts S, George J, Skoien R et al. (2016) RUBY-II: efficacy and safety of a ribavirin-free ombitasvir/paritaprevir/ritonavir ± dasabuvir regimen in patients with severe renal impairment or end-stage renal disease and HCV genotype 1a or 4 infection. American Association for the Study of Liver Diseases (AASLD); 11–15 November 2016; BostonGoogle Scholar
  27. 27.
    Copegus (ribavirin) (2015) [US Package Insert]. South San Francisco, CA, USA: Genentech Inc.Google Scholar
  28. 28.
    Polepally AR, Dutta S, Hu B, Podsadecki TJ, Awni WM, Menon RM (2016) Drug-drug interaction of omeprazole with the HCV direct-acting antiviral agents paritaprevir/ritonavir and ombitasvir with and without dasabuvir. Clin Pharmacol Drug Dev 5:269–277CrossRefGoogle Scholar
  29. 29.
    Lalezari J, Sullivan JG, Varunok P, Galen E, Kowdley KV, Rustgi V, Aguilar H, Felizarta F, McGovern B, King M, Polepally AR, Cohen DE (2015) Ombitasvir/paritaprevir/r and dasabuvir plus ribavirin in HCV genotype 1-infected patients on methadone or buprenorphine. J Hepatol 63:364–369CrossRefGoogle Scholar
  30. 30.
    Poordad F, Bennett M, Sepe TE, Cohen E, Reindollar RW, Everson G et al. (eds) (2015) QUARTZ-I: retreatment of HCV genotype 1 DAA-failures with ombitasvir/paritaprevir/r, dasabuvir, and sofosbuvir. American Association for the Study of Liver Diseases (AASLD); 13–17 November 2015; San FranciscoGoogle Scholar
  31. 31.
    Feld JJ, Moreno C, Trinh R, Tam E, Bourgeois S, Horsmans Y, Elkhashab M, Bernstein DE, Younes Z, Reindollar RW, Larsen L, Fu B, Howieson K, Polepally AR, Pangerl A, Shulman NS, Poordad F (2016) Sustained virologic response of 100% in HCV genotype 1b patients with cirrhosis receiving ombitasvir/paritaprevir/r and dasabuvir for 12 weeks. J Hepatol 64:301–307CrossRefGoogle Scholar
  32. 32.
    Menon RM, Badri PS, Wang T, Polepally AR, Zha J, Khatri A, Wang H, Hu B, Coakley EP, Podsadecki TJ, Awni WM, Dutta S (2015) Drug-drug interaction profile of the all-oral anti-hepatitis C virus regimen of paritaprevir/ritonavir, ombitasvir, and dasabuvir. J Hepatol 63:20–29CrossRefGoogle Scholar
  33. 33.
    Shebley M, Liu J, Kavetskaia O, Sydor J, de Morais SM, Fischer V, Nijsen MJMA, Bow DAJ (2017) Mechanisms and predictions of drug-drug interactions of the hepatitis C virus three direct-acting antiviral regimen: paritaprevir/ritonavir, ombitasvir, and dasabuvir. Drug Metab Dispos 45:755–764CrossRefGoogle Scholar
  34. 34.
    Glue P (1999) The clinical pharmacology of ribavirin. Semin Liver Dis 19(Suppl 1):17–24PubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Clinical Pharmacology and PharmacometricsAbbVie Inc.North ChicagoUSA

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