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Clinical Pharmacokinetics

, Volume 53, Issue 2, pp 141–153 | Cite as

Clinical Pharmacokinetic Drug Interactions Associated with Artemisinin Derivatives and HIV-Antivirals

  • Tony K. L. Kiang
  • Kyle J. Wilby
  • Mary H. H. Ensom
Review Article

Abstract

Management of HIV and malaria co-infection is challenging due to potential drug–drug interactions between antimalarial and HIV-antiviral drugs. Little is known of the clinical significance of these drug interactions, and this review provides a comprehensive summary and critical evaluation of the literature. Specifically, drug interactions between WHO-recommended artemisinin combination therapies (ACT) and HIV-antivirals are discussed. An extensive literature search produced eight articles detailing n = 44 individual pharmacokinetic interactions. Only data pertaining to artemether–lumefantrine and two other artesunate combinations are available, but most of the interactions are characterized on at least two occasions by two different groups. Overall, protease inhibitors (PIs) tended to increase the exposure of lumefantrine and decrease the exposures of artemether and dihydroartemisinin, a pharmacologically active metabolite of artemether. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) tended to decrease the exposures of artemether, dihydroartemisinin, and lumefantrine when co-administered with artemether–lumefantrine. Fewer studies characterized the effects of PIs or NNRTIs on artesunate combinations, but nevirapine increased artesunate exposure and ritonavir decreased dihydroartemisinin exposure. On the other hand, artemether–lumefantrine or artesunate combinations had little effect on the pharmacokinetics of HIV-antivirals, with the exception of decreased nevirapine exposure from artemether–lumefantrine or increased ritonavir exposure from pyronaridine/artesunate co-administration. In general, pharmacokinetic interactions can be explained by the metabolic properties of the co-administered drugs. Despite several limitations to the studies, these data do provide valuable insights into the potential pharmacokinetic perturbations, and the consistently marked elevation or reduction in ACT exposure in some cases cannot be overlooked.

Keywords

Malaria Artemisinin Ritonavir Efavirenz Nevirapine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

No sources of funding were used in the preparation of this review. Tony KL Kiang, Kyle J Wilby and Mary HH Ensom have no conflicts of interest to declare.

References

  1. 1.
    World Health Organization. Guidelines for the treatment of malaria. Second edition. March 2010. http://www.who.int/malaria/publications/atoz/9789241547925/en/index.html. Accessed 14 Jul 2013.
  2. 2.
    Joint United Nations Programme on HIV/AIDS (UNAIDS). AIDS epidemic update. December 2007. http://data.unaids.org/pub/EPISlides/2007/2007_epiupdate_en.pdf. Accessed 14 Jul 2013.
  3. 3.
    German P, Aweeka FT. Clinical pharmacology of artemisinin-based combination therapies. Clin Pharmacokinet. 2008;47:91–102.PubMedCrossRefGoogle Scholar
  4. 4.
    World Health Organization. Malaria and HIV and their implications for public policy, report of a technical consultation, Geneva, Switzerland, 23–25 June 2004. http://www.who.int/hiv/pub/prev_care/malariahiv.pdf. Accessed 14 Jul 2013.
  5. 5.
    Chalwe V, Van Geertruyden JP, Mukwamataba D, et al. Increased risk for severe malaria in HIV-1-infected adults, Zambia. Emerg Infect Dis. 2009;15:749–55.PubMedCrossRefGoogle Scholar
  6. 6.
    Grimwade K, French N, Mbatha DD, et al. HIV infection as a cofactor for severe falciparum malaria in adults living in a region of unstable malaria transmission in South Africa. AIDS. 2004;18:547–54.PubMedCrossRefGoogle Scholar
  7. 7.
    Ayisi JG, van Eijk AM, ter Kuile FO, et al. The effect of dual infection with HIV and malaria on pregnancy outcome in western Kenya. AIDS. 2003;17:585–94.PubMedCrossRefGoogle Scholar
  8. 8.
    Bloland PB, Wirima JJ, Steketee RW, et al. Maternal HIV infection and infant mortality in Malawi: evidence for increased mortality due to placental malaria infection. AIDS. 1995;9:721–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Van Geertruyden JP, Mulenga M, Mwananyanda L, et al. HIV-1 immune suppression and antimalarial treatment outcome in Zambian adults with uncomplicated malaria. J Infect Dis. 2006;194:917–25.PubMedCrossRefGoogle Scholar
  10. 10.
    Kublin JG, Patnaik P, Jere CS, et al. Effect of Plasmodium falciparum malaria on concentration of HIV-1-RNA in the blood of adults in rural Malawi: a prospective cohort study. Lancet. 2005;365:233–40.PubMedGoogle Scholar
  11. 11.
    Khoo S, Back D, Winstanley P. The potential for interactions between antimalarial and antiretroviral drugs. AIDS. 2005;19:995–1005.PubMedCrossRefGoogle Scholar
  12. 12.
    The Department for Health and Human Services [DHHS] guidelines Panel on antiretroviral guidelines for adults and adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents; Feb 2013. http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf. Accessed 14 Jul 2013.
  13. 13.
    Byakika-Kibwika P, Lamorde M, Mayanja-Kizza H, et al. Update on the efficacy, effectiveness and safety of artemether–lumefantrine combination therapy for treatment of uncomplicated malaria. Ther Clin Risk Manag. 2010;6:11–20.PubMedCentralPubMedGoogle Scholar
  14. 14.
    Giao PT, de Vries PJ. Pharmacokinetic interactions of antimalarial agents. Clin Pharmacokinet. 2001;40:343–73.PubMedCrossRefGoogle Scholar
  15. 15.
    Medhi B, Patyar S, Rao RS, et al. Pharmacokinetic and toxicological profile of artemisinin compounds: an update. Pharmacology. 2009;84:323–32.PubMedCrossRefGoogle Scholar
  16. 16.
    Nsanzabana C, Rosenthal P. In vitro activity of antiretroviral drugs against Plasmodium falciparum. Antimicrob Agents Chemother. 2011;55:5073–7.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    German P, Parikh S, Lawrence J, et al. Lopinavir/ritonavir affects pharmacokinetic exposure of artemether/lumefantrine in HIV-uninfected healthy volunteers. J Acquir Immune Defic Syndr. 2009;51:424–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Byakika-Kibwika P, Lamorde M, Okaba-Kayom V, et al. Lopinavir/ritonavir significantly influences pharmacokinetic exposure of artemether/lumefantrine in HIV-infected Ugandan adults. J Antimicrob Chemother. 2012;67:1217–23.PubMedCrossRefGoogle Scholar
  19. 19.
    Kakuda T, Demasi R, van Delft Y, et al. Pharmacokinetic interaction between etravirine or darunavir/ritonavir and artemether/lumefantrine in healthy volunteers: a two-panel, two-way, two-period, randomized trial. HIV Med. 2013;14:421–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Wyen C, Fuhr U, Frank D, et al. Effect of an antiretroviral regimen containing ritonavir boosted lopinavir on intestinal and hepatic CYP3A, CYP2D6 and P-glycoprotein in HIV-infected patients. Clin Pharmacol Ther. 2008;84:75–82.PubMedCrossRefGoogle Scholar
  21. 21.
    McKeage K, Perry CM, Keam SJ. Darunavir: a review of its use in the management of HIV infection in adults. Drugs. 2009;69:477–503.PubMedCrossRefGoogle Scholar
  22. 22.
    Lefevre G, Carpenter P, Souppart C, et al. Pharmacokinetics and electrocardiographic pharmacodynamics of artemether–lumefantrine (Riamet) with concomitant administration of ketoconazole in healthy subjects. Br J Clin Pharmacol. 2002;54:485–92.PubMedCrossRefGoogle Scholar
  23. 23.
    van Agtmael MA, Cheng-Qi S, Qing JX, et al. Multiple dose pharmacokinetics of artemether in Chinese patients with uncomplicated falciparum malaria. Int J Antimicrob Agents. 1999;12:151–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Yeh RF, Gaver VE, Patterson KB, et al. Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers. J Acquir Immune Defic Syndr. 2006;42:52–60.PubMedGoogle Scholar
  25. 25.
    Foisy MM, Yakiwchuk EM, Hughes CA. Induction effects of ritonavir: implications for drug interactions. Ann Pharmacother. 2008;42:1048–59.PubMedCrossRefGoogle Scholar
  26. 26.
    Ilett KF, Ethell BT, Maggs JL, et al. Glucuronidation of dihydroartemisinin in vivo and by human liver microsomes and expressed UDP-glucuronosyltransferases. Drug Metab Dispos. 2002;30:1005–12.PubMedCrossRefGoogle Scholar
  27. 27.
    Zhang D, Chando TJ, Everett DW, et al. In vitro inhibition of UDP glucuronosyltransferases by atazanavir and other HIV protease inhibitors and the relationship of this property to in vivo bilirubin glucuronidation. Drug Metab Dispos. 2005;33:1729–39.PubMedCrossRefGoogle Scholar
  28. 28.
    Price RN, Uhlemann AC, van Vugt M, et al. Molecular and pharmacological determinants of the therapeutic response to artemether–lumefantrine in multidrug-resistant Plasmodium falciparum malaria. Clin Infect Dis. 2006;42:1570–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Byakika-Kibwika P, Lamorde M, Lwabi P, et al. Cardiac conduction safety during coadministration of artemether–lumefantrine and lopinavir/ritonavir in HIV-infected Ugandan adults. Chemother Res Pract. 2011;2011:1–4.CrossRefGoogle Scholar
  30. 30.
    Byakika-Kibwika P, Lamorde M, Mayito J, et al. Significant pharmacokinetic interactions between artemether/lumefantrine and efavirenz or nevirapine in HIV-infected Ugandan adults. J Antimicrob Chemother. 2012;69:2213–21.CrossRefGoogle Scholar
  31. 31.
    Huang L, Parikh S, Rosenthal PJ, et al. Concomitant efavirenz reduces pharmacokinetic exposure to the antimalarial drug artemether–lumefantrine in healthy volunteers. J Acquir Immune Defic Syndr. 2012;61:310–6.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Kredo T, Mauff K, Van der Walt JS, et al. Interaction between artemether–lumefantrine and nevirapine-based antiretroviral therapy in HIV-1-infected patients. Antimicrob Agents Chemother. 2011;55:5616–23.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Hariparsad N, Nallani SC, Sane RS, et al. Induction of CYP3A4 by efavirenz in primary human hepatocytes: comparison with rifampin and phenobarbital. J Clin Pharmacol. 2004;44:1273–81.PubMedCrossRefGoogle Scholar
  34. 34.
    Faucette SR, Zhang TC, Moore R, et al. Relative activation of human pregnane X receptor versus constitutive androstane receptor defines distinct classes of CYP2B6 and CYP3A4 inducers. J Pharmacol Exp Ther. 2007;320:72–80.PubMedCrossRefGoogle Scholar
  35. 35.
    Yanakakis LJ, Bumpus NN. Biotransformation of the antiretroviral drug etravirine: metabolite identification, reaction phenotyping, and characterization of autoinduction of cytochrome P450-dependent metabolism. Drug Metab Dispos. 2012;40:803–14.PubMedCrossRefGoogle Scholar
  36. 36.
    Lamorde M, Byakika-Kibwika P, Mayito J, et al. Lower artemether, dihydroartemisinin and lumefantrine concentrations during rifampicin-based tuberculosis treatment. AIDS. 2013;27:961–5.PubMedCrossRefGoogle Scholar
  37. 37.
    Fehintola FA, Scarsi KK, Ma Q, et al. Nevirapine-based antiretroviral therapy impacts artesunate and dihydroartemisinin disposition in HIV-infected Nigerian adults. AIDS Res Treat. 2012;2012:1–6.CrossRefGoogle Scholar
  38. 38.
    Morris CA, Lopez-Lazaro L, Jung D, et al. Drug–drug interaction analysis of pyronaridine/artesunate and ritonavir in healthy volunteers. Am J Trop Med Hyg. 2012;86:489–95.PubMedCrossRefGoogle Scholar
  39. 39.
    Li XQ, Bjorkman A, Andersson TB, et al. Identification of human cytochrome P(450)s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data. Eur J Clin Pharmacol. 2003;59:429–42.PubMedCrossRefGoogle Scholar
  40. 40.
    Lamson M, MacGregor T, Riska P, et al. Nevirapine induces both CYP3A4 and CYP2B6 metabolic pathways. Clin Pharmacol Ther. 1999;65:137.CrossRefGoogle Scholar
  41. 41.
    Aarnoutse RE, Kleinnijenhuis J, Koopmans PP, et al. Effect of low-dose ritonavir (100 mg twice daily) on the activity of cytochrome P450 2D6 in healthy volunteers. Clin Pharmacol Ther. 2005;78:664–74.PubMedCrossRefGoogle Scholar
  42. 42.
    Croft SL, Duparc S, Arbe-Barnes SJ, et al. Review of pyronaridine anti-malarial properties and product characteristics. Malar J. 2012;11:270–98.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Teja-Isavadharm P, Watt G, Eamsila C, et al. Comparative pharmacokinetics and effect kinetics of orally administered artesunate in healthy volunteers and patients with uncomplicated falciparum malaria. Am J Trop Med Hyg. 2001;65:717–21.PubMedGoogle Scholar
  44. 44.
    Dickinson L, Khoo S, Back D, et al. Differences in the pharmacokinetics of protease inhibitors between healthy volunteers and HIV-infected persons. Curr Opin HIV AIDS. 2008;3:296–305.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  • Tony K. L. Kiang
    • 1
  • Kyle J. Wilby
    • 2
  • Mary H. H. Ensom
    • 1
    • 3
  1. 1.Faculty of Pharmaceutical SciencesThe University of British ColumbiaVancouverCanada
  2. 2.College of PharmacyQatar UniversityDohaQatar
  3. 3.Pharmacy Department (0B7)Children’s and Women’s Health Centre of British ColumbiaVancouverCanada

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