Skip to main content
SpringerLink
Log in

Clinical Pharmacokinetics of Dasabuvir

  • Review Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Dasabuvir is a nonstructural (NS) 5B non-nucleoside inhibitor of the hepatitis C virus (HCV) used in combination with ombitasvir/paritaprevir/ritonavir for the treatment of chronic HCV infection. It is primarily metabolized by cytochrome P450 (CYP) 2C8, with a minor contribution from CYP3A. Biotransformation of dasabuvir forms the M1 metabolite, which retains antiviral activity. Dasabuvir exhibits linear pharmacokinetics with a terminal half-life of approximately 5–8 h, allowing for twice-daily dosing. The M1 metabolite of dasabuvir is the major metabolite in plasma and has a half-life similar to that of dasabuvir. Dasabuvir exposures in Asian subjects are comparable with Caucasian subjects. The pharmacokinetic characteristics of dasabuvir are similar between healthy subjects and HCV-infected patients, and are not appreciably altered by mild, moderate, or severe renal impairment or dialysis. Dasabuvir pharmacokinetic parameters were not significantly altered in subjects with mild or moderate hepatic impairment; however, exposures were significantly increased in subjects with severe hepatic impairment. Dasabuvir should be administered with food to maximize absorption. Coadministration of dasabuvir with a strong CYP2C8 inhibitor increased dasabuvir exposures by greater than tenfold, whereas coadministration with strong CYP3A inhibitors increased dasabuvir exposures by less than 50%. Furthermore, coadministration of dasabuvir with a CYP3A inducer decreased dasabuvir exposures by 55–70%. Coadministration of dasabuvir with strong CYP2C8 inhibitors or strong CYP3A/CYP2C8 inducers is contraindicated. Results from several drug interaction studies demonstrated that dasabuvir in combination with ombitasvir/paritaprevir/ritonavir can be coadministered with most comedications that are commonly prescribed in HCV-infected patients.

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. Kati W, Koev G, Irvin M, Beyer J, Liu Y, Krishnan P, et al. In vitro activity and resistance profile of dasabuvir, a nonnucleoside hepatitis C virus polymerase inhibitor. Antimicrob Agents Chemother. 2015;59(3):1505–11.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Viekira Pak (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets) [US package insert]. North Chicago: AbbVie Inc.; 2016.

  3. Exviera (dasabuvir) [summary of product characteristics]. Maidenhead: AbbVie Ltd.; 2016.

  4. 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(17):1594–603.

    Article  CAS  PubMed  Google Scholar 

  5. 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(21):1983–92.

    Article  PubMed  Google Scholar 

  6. 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(17):1604–14.

    Article  CAS  PubMed  Google Scholar 

  7. 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(9986):2502–9.

    Article  CAS  PubMed  Google Scholar 

  8. 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(2):359 e1–365 e1.

    Article  Google Scholar 

  9. Feld JJ, Moreno C, Trinh R, Tam E, Bourgeois S, Horsmans Y, et al. Sustained virologic response of 100% in HCV genotype 1b patients with cirrhosis receiving ombitasvir/paritaprevir/r and dasabuvir for 12 weeks. J Hepatol. 2016;64(2):301–7.

    Article  CAS  PubMed  Google Scholar 

  10. Menon RM, Polepally AR, Khatri A, Awni WM, Dutta S. Clinical pharmacokinetics of paritaprevir. Clin Pharmacokinet. doi:10.1007/s40262-017-0520-x.

  11. Badri PS, Shuster DL, Dutta S, Menon RM. Clinical pharmacokinetics of ombitasvir. Clin Pharmacokinet. doi:10.1007/s40262-017-0518-4.

  12. Holkira Pak (ombitasvir/pritaprevir/ritonavir and dasabuvir) product monograph. St-Laurent: AbbVie Corp.; 2016.

  13. Khatri A, Menon RM, Marbury TC, Lawitz EJ, Podsadecki TJ, Mullally VM, et al. Pharmacokinetics and safety of co-administered paritaprevir plus ritonavir, ombitasvir, and dasabuvir in hepatic impairment. J Hepatol. 2015;63(4):805–12.

    Article  CAS  PubMed  Google Scholar 

  14. Khatri A, Dutta S, Marbury T, Preston RA, Rodrigues L Jr, Wang H, 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. 2017;56(2):153–63.

    Article  CAS  PubMed  Google Scholar 

  15. Bow DAJ, Liu J, Kavetskaia O, Menon R, de Morais SM, Nijsen M. A mechanistic non-clinical assessment of drug-drug interactions (metabolism and transporters) with the hepatitis C virus (HCV) regimen: ABT-450/r, ombitasvir and dasabuvir. AASLD/EASL Special Conference on Hepatitis C. New York, NY, 3–5 October 2014.

  16. Shen J, Serby M, Reed A, Lee AJ, Menon R, Zhang X, et al. Metabolism and disposition of hepatitis C polymerase inhibitor dasabuvir in humans. Drug Metab Dispos. 2016;44(8):1139–47.

    Article  CAS  PubMed  Google Scholar 

  17. US FDA. FDA hepatitis update—approval of VIEKIRA XR extended release fixed dose combination tablets. https://content.govdelivery.com/accounts/USFDA/bulletins/158dd48. Accessed 16 Jan 2017.

  18. Viekira XR (dasabuvir, ombitasvir, paritaprevir, and ritonavir extended release tablets) package insert. North Chicago: AbbVie Inc.; 2016.

  19. US FDA, Center for Drug Evaluation and Research. Application number 206619Orig1s000. Summary review. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206619Orig1s000SumR.pdf. Accessed 16 Jan 2017.

  20. Polepally AR, Badri PS, Eckert D, Mensing S, Menon RM. 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. doi:10.1007/s13318-016-0341-6.

  21. Pockros PJ, Reddy KR, Mantry PS, Cohen E, Bennett M, Sulkowski MS, et al. 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. 2016;150(7):1590–8.

    Article  CAS  PubMed  Google Scholar 

  22. Shuster DL, Menon RM, Ding B, Li H, Cohen E, Cohen DE, et al. Ombitasvir, paritaprevir, ritonavir, dasabuvir and ribavirin pharmacokinetics in HCV-infected subjects with chronic kidney disease stage 4 (severe renal impairment) or stage 5 (end-stage renal disease). Hepatology. 2016;64(1 Suppl):975A.

    Google Scholar 

  23. Mensing S, Eckert D, Sharma S, Polepally AR, Khatri A, Podsadecki TJ, et al. Population pharmacokinetics of paritaprevir, ombitasvir, dasabuvir, ritonavir and ribavirin in hepatitis C virus genotype 1 infection: analysis of six phase III trials. Br J Clin Pharmacol. doi:10.1111/bcp.13138.

  24. Khatri A, Mensing S, Podsadecki T, Awni W, Menon R, Dutta S. Exposure-efficacy analyses of ombitasvir, paritaprevir/ritonavir with dasabuvir ± ribavirin in HCV genotype 1-infected patients. Clin Drug Investig. 2016;36(8):625–35.

    Article  CAS  PubMed  Google Scholar 

  25. Menon RM, Badri PS, Wang T, Polepally AR, Zha J, Khatri A, et al. Drug–drug interaction profile of the all-oral anti-hepatitis C virus regimen of paritaprevir/ritonavir, ombitasvir, and dasabuvir. J Hepatol. 2015;63(1):20–9.

    Article  CAS  PubMed  Google Scholar 

  26. Badri PS, Dutta S, Wang H, Podsadecki TJ, Polepally AR, Khatri A, et al. Drug interactions with the direct-acting antiviral combination of ombitasvir and paritaprevir-ritonavir. Antimicrob Agents Chemother. 2015;60(1):105–14.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Polepally AR, King JR, Ding B, Shuster DL, Dumas EO, Khatri A, et al. Drug–drug interactions between the anti-hepatitis C virus 3D regimen of ombitasvir, paritaprevir/ritonavir, and dasabuvir and eight commonly used medications in healthy volunteers. Clin Pharmacokinet. 2016;55(8):1003–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Khatri A, Dutta S, Wang H, Podsadecki T, Trinh R, Awni W, et al. Evaluation of drug–drug interactions between hepatitis C antiviral agents ombitasvir, paritaprevir/ritonavir, and dasabuvir and HIV-1 protease inhibitors. Clin Infect Dis. 2016;62(8):972–9.

    Article  PubMed  Google Scholar 

  29. King JR, Dutta S, Cohen D, Podsadecki TJ, Ding B, Awni WM, et al. Drug–drug interactions between sofosbuvir and ombitasvir–paritaprevir–ritonavir with or without dasabuvir. Antimicrob Agents Chemother. 2015;60(2):855–61.

    Article  PubMed  Google Scholar 

  30. Zha J, Badri PS, Ding B, Uchiyama N, Alves K, Rodrigues-Jr L, et al. Drug interactions between hepatoprotective agents ursodeoxycholic acid or glycyrrhizin and ombitasvir/paritaprevir/ritonavir in healthy japanese subjects. Clin Ther. 2015;37(11):2560–71.

    Article  CAS  PubMed  Google Scholar 

  31. Badri P, Dutta S, Coakley E, Cohen D, Ding B, Podsadecki T, et al. Pharmacokinetics and dose recommendations for cyclosporine and tacrolimus when coadministered with ABT-450, ombitasvir, and dasabuvir. Am J Transplant. 2015;15(5):1313–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Badri PS, King JR, Polepally AR, McGovern BH, Dutta S, Menon RM. Dosing recommendations for concomitant medications during 3D anti-HCV therapy. Clin Pharmacokinet. 2016;55(3):275–95.

    Article  CAS  PubMed  Google Scholar 

  33. Khatri A, Trinh R, Zhao W, Podsadecki T, Menon R. Drug–drug interaction between the direct-acting antiviral regimen of ombitasvir/paritaprevir/ritonavir plus dasabuvir and the hiv antiretroviral agents dolutegravir or abacavir plus lamivudine. Antimicrob Agents Chemother. 2016;60(10):6244–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank AbbVie employee Amy K. Rohrlack for medical writing support.

Author information

Authors and Affiliations

  1. Clinical Pharmacology and Pharmacometrics, Dept. R4PK, Bldg. AP31-3, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA

    Jennifer R. King, Jiuhong Zha, Amit Khatri, Sandeep Dutta & Rajeev M. Menon

Authors
  1. Jennifer R. King
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jiuhong Zha
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amit Khatri
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sandeep Dutta
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rajeev M. Menon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rajeev M. Menon.

Ethics declarations

Funding

The studies summarized in this report were supported by AbbVie, who contributed to the study designs, research, and interpretation of data, and the writing, reviewing, and approving of the publication.

Conflicts of interest

Jennifer R. King, Jiuhong Zha, Amit Khatri, Sandeep Dutta, and Rajeev M. Menon are current or former AbbVie employees and may own AbbVie stock or stock options.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

King, J.R., Zha, J., Khatri, A. et al. Clinical Pharmacokinetics of Dasabuvir. Clin Pharmacokinet 56, 1115–1124 (2017). https://doi.org/10.1007/s40262-017-0519-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-017-0519-3

Keywords

Search

Navigation