Skip to main content
SpringerLink
Log in

Pharmacokinetics of Darunavir (TMC114) and Atazanavir during Coadministration in HIV-Negative, Healthy Volunteers

  • Original Research Article
  • Published:
Drugs in R & D Aims and scope Submit manuscript

Abstract

Background and objective: To investigate the potential for pharmacokinetic interactions between the protease inhibitors darunavir (DRV, TMC114) coadministered with low-dose ritonavir (darunavir/r), and atazanavir in HIVnegative, healthy volunteers.

Methods: This was an open-label, randomised, three-period, crossover study. Darunavir/r (400/100mg twice daily), atazanavir/r (300/100mg once daily) or darunavir/r (400/100mg twice daily) plus atazanavir (300mg once daily) were administered in three separate sessions, with a washout period of at least 7 days between regimens. The follow-up lasted 30 days. Twenty-three healthy volunteers participated. Pharmacokinetic assessments were performed at steady-state on day 7. Plasma drug concentrations were determined by liquid chromatography-tandem mass spectrometry and pharmacokinetic parameters were compared between treatments. The safety and tolerability of the study medications were monitored throughout.

Results: Darunavir pharmacokinetics were unaffected by atazanavir. No change in overall exposure to atazanavir was observed during coadministration with darunavir/r. However, there was a 52% increase in minimum atazanavir plasma concentration (least squares mean ratio [90% CI 0.99, 2.34]). Mean systemic exposure to ritonavir was increased by 65% and 106%, respectively, with the combination treatment compared with darunavir/r alone or atazanavir/r alone. There were no apparent differences in mean changes in lipids between the darunavir/r, atazanavir/r or darunavir/r plus atazanavir regimens. Hyperbilirubinaemia and ocular icterus were reported with atazanavir-containing regimens.

Conclusion: Atazanavir at a dose of 300mg once daily can be coadministered with a darunavir/r twice-daily regimen without any dose adjustment if there is a clinical need to combine darunavir/r and atazanavir in HIV-1-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
Fig. 3
Table I
Table II
Table III
Table IV

Similar content being viewed by others

References

  1. De Meyer S, Azijn H, Surleraux D, et al. TMC114, a novel human immunodeficiency virus type 1 protease inhibitor active against protease inhibitor-resistant viruses, including a broad range of clinical isolates. Antimicrob Agents Chemother 2005; 49: 2314–21

    Article  PubMed  Google Scholar 

  2. Katlama C, Esposito R, Gatell J, et al. Efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients: 24-week results of POWER 1. AIDS 2007; 21: 395–402

    Article  PubMed  CAS  Google Scholar 

  3. Haubrich R, Berger D, Chiliade P, et al. Week 24 efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients: POWER 2. AIDS 2007; 21 (6): F11–8

    Article  PubMed  Google Scholar 

  4. Molina JM, Cohen C, Katlama C, et al. POWER 3: 24-week efficacy and safety results of TMC114/r in treatment-experienced patients [abstract P4]. HIV Med 2006; 7 Suppl. 1: 12

    Google Scholar 

  5. Prezista® (darunavir) prescribing information [online]. Tibotec Therapeutics, Raritan, New Jersey, USA. October 2006. Available from URL: http://www.prezista.com/docs/us_pack-age_insert.pdf [Accessed 2006 Oct 20].

    Google Scholar 

  6. Sekar V, Spinosa-Guzman S, Lefebvre E, et al. Clinical Pharmacology of TMC114: a potent HIV protease inhibitor [abstract TUPE0083]. 16th International AIDS Conference; 2006 August 13–19; Toronto

    Google Scholar 

  7. Reyataz® (atazanavir sulfate) prescribing information [online]. Bristol-Meyers Squibb Company, Princeton, New Jersey, USA. October 2006. Available from URL: http://www.bms.com/cgi-bin/anybin.pl?.sql=select%20PPI20from%20TB_PRODUCT_PPI%20where%20PPI_SEQ=103&key=PPI [Accessed 2006 Oct 16]

    Google Scholar 

  8. Staszewski S, Babacan E, Stephan C, et al. The LOPSAQ study: 48 week analysis of a boosted double protease inhibitor regimen containing lopinavir/ritonavir plus saquinavir without additional antiretroviral therapy. J Antimicrob Chemother 2006; 58 (5): 1024–30

    Article  PubMed  CAS  Google Scholar 

  9. Ribera E, Azuaje C, Lopez RM, et al. Atazanavir and lopinavir/ritonavir: pharmacokinetics, safety and efficacy of a promising double-boosted protease inhibitor regimen. AIDS 2006; 20 (8): 1131–9

    Article  PubMed  CAS  Google Scholar 

  10. Boffito M, Moyle GJ. Pharmacokinetic considerations for combining 2 protease inhibitors. AIDS Read 2004; 14: 110–112, 115-110-2, 116

    PubMed  Google Scholar 

  11. Grading severity of adult adverse experiences, Division of AIDS 1992 [online]. Available from URL: http://www.rcc.tech-res.com/tox_tables [Accessed 2007 May 29]

    Google Scholar 

  12. Koch G. The use of nonparametric methods in the statistical analysis of the two-period change-over design. Biometrics 1972; 28: 577–84

    Article  PubMed  CAS  Google Scholar 

  13. Molla A, Mo H, Vasavanonda S, et al. In vitro antiviral interaction of lopinavir with other protease inhibitors. Antimicrob Agents Chemother 2002; 46: 2249–53

    Article  PubMed  CAS  Google Scholar 

  14. Bulgheroni E, Citterio P, Croce F, et al. Analysis of protease inhibitor combinations in vitro: activity of lopinavir, amprenavir and tipranavir against HIV type 1 wild-type and drugresistant isolates. J Antimicrob Chemother 2004; 53: 464–8

    Article  PubMed  CAS  Google Scholar 

  15. Piscitelli SC, Gallicano KD. Interactions among drugs for HIV and opportunistic infections. N Engl J Med 2001; 344: 984–96

    Article  PubMed  CAS  Google Scholar 

  16. Boffito M, Maitland D, Samarasinghe Y, et al. The pharmacokinetics of HIV protease inhibitor combinations. Curr Opin Infect Disease 2005; 18: 1–7

    Article  CAS  Google Scholar 

  17. Walmsley S, Leith J, Katlama C, et al. Pharmacokinetics and safety of tipranavir/ritonavir (TPV/r) alone or in combination with saquinavir (SQV), amprenavir (APV), or lopinavir (LPV): interim analysis of BI1182.51 [abstract WeOrB1236]. 15th International AIDS Conference; 2004 Jul 11–16; Bangkok

    Google Scholar 

  18. Boffito M, Dickinson L, Hill A, et al. Steady-state pharmacokinetics of saquinavir hard-gel/ritonavir/fosamprenavir in HIV-1-infected patients. J Acquir Immune Defic Syndr 2004; 37: 1376–84

    Article  PubMed  CAS  Google Scholar 

  19. Stephan C, Hentig N, Kourbeti I, et al. Saquinavir drug exposure is not impaired by the boosted double protease inhibitor combination of lopinavir/ritonavir. AIDS 2004; 18: 503–8

    Article  PubMed  CAS  Google Scholar 

  20. Ribera E, Lopez RM, Diaz M, et al. Steady-state pharmacokinetics of a double-boosting regimen of saquinavir nodeficiency virus-infected adults. Antimicrob Agents Chemother 2004; 48: 4256–62

    Article  PubMed  CAS  Google Scholar 

  21. Boffito M, Kurowski M, Kruse G, et al. Atazanavir enhances saquinavir hard-gel concentrations in a ritonavir-boosted oncedaily regimen. AIDS 2004; 18: 1291–7

    Article  PubMed  CAS  Google Scholar 

  22. Boffito M, Maitland D, Dickinson L, et al. Pharmacokinetics of saquinavir hard gel (SQV)/ritonavir and atazanavir when combined once daily in HIV type 1-infected individuals administered different atazanavir doses. AIDS Res Hum Retroviruses 2006; 22: 749–56

    Article  PubMed  CAS  Google Scholar 

  23. Gonzalez Rodriguez-Novoa S, Martin-Carbonero L, Barreiro P, et al. Genetic factors influencing atazanavir plasma concentrations and the risk of severe hyperbilirubinemia. AIDS 2007; 21: 41–6

    Article  Google Scholar 

Download references

Acknowledgements

This study was funded by Tibotec. All the authors are employees of Tibotec. These data were presented in part at the 10th European AIDS Conference, Dublin, Ireland, 17–20 November 2005.

Author information

Authors and Affiliations

  1. Tibotec Inc., Yardley, Pennsylvania, USA

    Vanitha J. Sekar, Eric Lefebvre & Tine De Marez

  2. Tibotec BVBA, Mechelen, Belgium

    Sabrina Spinosa-Guzman, Martine De Pauw, Els De Paepe, Tony Vangeneugden &  Richard M. W. Hoetelmans

Authors
  1. Vanitha J. Sekar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eric Lefebvre
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tine De Marez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sabrina Spinosa-Guzman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Martine De Pauw
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Els De Paepe
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tony Vangeneugden
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Richard M. W. Hoetelmans
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Richard M. W. Hoetelmans.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sekar, V.J., Lefebvre, E., De Marez, T. et al. Pharmacokinetics of Darunavir (TMC114) and Atazanavir during Coadministration in HIV-Negative, Healthy Volunteers. Drugs R D 8, 241–248 (2007). https://doi.org/10.2165/00126839-200708040-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00126839-200708040-00004

Keywords

Search

Navigation