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Pharmacologic aspects of new antiretroviral drugs

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Abstract

The biggest challenge facing highly antiretroviral-experienced patients and their caregivers is the diminishing number of therapeutic options available that sustain activity despite increasing numbers of drug-resistance mutations. New options in antiretroviral treatment have been introduced: two new members of traditional antiretroviral classes (darunavir and etravirine) and two drugs with novel mechanisms of action (raltegravir and maraviroc). Each was approved for use in treatment-experienced patients. A fifth drug—containing efavirenz, tenofovir, and emtricitabine (Atripla; Bristol-Myers Squibb, New York, NY, and Gilead Sciences, Foster City, CA)—is a novel coformulation of existing drugs from two different classes, simplifying administration with the intent of increasing adherence. Because successful management of HIV infection requires the simultaneous use of three or more drugs, understanding the pharmacologic aspects of coadministration is critical. This review summarizes the pharmacokinetic properties affecting the administration of these recently approved drugs in light of highly active antiretroviral treatment guidelines.

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References and Recommended Reading

  1. Perno CF, Moyle G, Tsoukas C, et al.: Overcoming resistance to existing therapies in HIV-infected patients: the role of new antiretroviral drugs. J Med Virol 2008, 80:565–576.

    Article  PubMed  CAS  Google Scholar 

  2. Department of Health and Human Services; Panel on Antiretroviral Guidelines for Adults and Adolescents: Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed February 2008.

  3. Martinez-Cajas JL, Wainberg MA: Antiretroviral therapy: optimal sequencing of therapy to avoid resistance. Drugs 2008, 68:43–72.

    PubMed  CAS  Google Scholar 

  4. Bartlett JG: Antiretroviral therapy. In A Guide to Primary Care of People With HIV/AIDS. Edited by Bartlett JG, Cheever LW, Johnson MP, Paauw DS. Rockville, MD: Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau; 2004.

    Google Scholar 

  5. Krakovska O, Wahl LM: Optimal drug treatment regimens for HIV depend on adherence. J Theor Biol 2007, 246:499–509.

    Article  PubMed  CAS  Google Scholar 

  6. Paterson DL, Swindells S, Mohr J, et al.: Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med 2000, 133:21–30.

    PubMed  CAS  Google Scholar 

  7. McCoy C: Darunavir: a nonpeptidic antiretroviral protease inhibitor. Clin Ther 2007, 29:1559–1576.

    Article  PubMed  CAS  Google Scholar 

  8. Rittweger M, Arasteh K: Clinical pharmacokinetics of darunavir. Clin Pharmacokinet 2007, 46:739–756.

    Article  PubMed  CAS  Google Scholar 

  9. King JR, Wynn H, Brundage R, Acosta EP: Pharmacokinetic enhancement of protease inhibitor therapy. Clin Pharmacokinet 2004, 43:291–310.

    Article  PubMed  CAS  Google Scholar 

  10. Youle M: Overview of boosted protease inhibitors in treatment-experienced HIV-infected patients. J Antimicrob Chemother 2007, 60:1195–1205.

    Article  PubMed  CAS  Google Scholar 

  11. Ford J, Khoo SH, Back DJ: The intracellular pharmacology of antiretroviral protease inhibitors. J Antimicrob Chemother 2004, 54:982–990.

    Article  PubMed  CAS  Google Scholar 

  12. Temesgen Z, Feinberg J: Tipranavir: a new option for the treatment of drug-resistant HIV infection. Clin Infect Dis 2007, 45:761–769.

    Article  PubMed  CAS  Google Scholar 

  13. Boffito M, Back DJ, Blaschke TF, et al.: Protein binding in antiretroviral therapies. AIDS Res Hum Retroviruses 2003, 19:825–835.

    Article  PubMed  CAS  Google Scholar 

  14. Schon A, del Mar Ingaramo M, Freire E: The binding of HIV-1 protease inhibitors to human serum proteins. Biophys Chem 2003, 105:221–230.

    Article  PubMed  CAS  Google Scholar 

  15. Clotet B, Bellos N, Molina JM, et al.: Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials. Lancet 2007, 369:1169–1178.

    Article  PubMed  CAS  Google Scholar 

  16. Sekar VJ, Lefebvre E, Marien K, et al.: Pharmacokinetic interaction between darunavir and saquinavir in HIV-negative volunteers. Ther Drug Monit 2007, 29:795–801.

    Article  PubMed  CAS  Google Scholar 

  17. Boffito M, Winston A, Jackson A, et al.: Pharmacokinetics and antiretroviral response to darunavir/ritonavir and etravirine combination in patients with high-level viral resistance. AIDS 2007, 21:1449–1455.

    Article  PubMed  CAS  Google Scholar 

  18. Smith PF, DiCenzo R, Morse GD: Clinical pharmacokinetics of nonnucleoside reverse transcriptase inhibitors. Clin Pharmacokinet 2001, 40:893–905.

    Article  PubMed  CAS  Google Scholar 

  19. Jochmans D: Novel HIV-1 reverse transcriptase inhibitors. Virus Res 2008, 134:171–185.

    Article  PubMed  CAS  Google Scholar 

  20. Hodder S: Know your patient: what conditions affect initial HIV treatment success? J Int Assoc Physicians AIDS Care 2008, 7(Suppl 1):S5–S9.

    Article  Google Scholar 

  21. Back DJ, Burger DM, Flexner CW, Gerber JG: The pharmacology of antiretroviral nucleoside and nucleotide reverse transcriptase inhibitors: implications for once-daily dosing. J Acquir Immune Defic Syndr 2005, 39(Suppl 1):S1–S25.

    PubMed  CAS  Google Scholar 

  22. Reisler R: NNRTI’s: New Insights-—“The NNRTI TAIL”; drug resistance; prevention of mother-to-child HIV transmission; HAART interruption. In Conference Reports for NATAP. Edited by Levin J. New York: National AIDS Treatment Advocacy Project; 2004:1–3.

    Google Scholar 

  23. Gazzard BG, Pozniak AL, Rosenbaum W, et al.: An open-label assessment of TMC 125-a new, next-generation NNRTI, for 7 days in HIV-1 infected individuals with NNRTI resistance. AIDS 2003, 17:F49–F54.

    Article  PubMed  CAS  Google Scholar 

  24. Magiorkinis E, Paraskevis D, Sambatakou H, et al.: Emergence of an NNRTI resistance mutation Y181C in an HIV-infected NNRTI-naive patient. AIDS Res Hum Retroviruses 2008, 24:413–415.

    Article  PubMed  CAS  Google Scholar 

  25. Hachiya A, Kodama EN, Sarafianos SG, et al.: Amino acid mutation N348I in the connection subdomain of human immunodeficiency virus type 1 reverse transcriptase confers multiclass resistance to nucleoside and nonnucleoside reverse transcriptase inhibitors. J Virol 2008, 82:3261–3270.

    Article  PubMed  CAS  Google Scholar 

  26. Andries K, Azijn H, Thielemans T, et al.: TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother 2004, 48:4680–4686.

    Article  PubMed  CAS  Google Scholar 

  27. Poveda E, Garrido C, de Mendoza C, et al.: Prevalence of etravirine (TMC-125) resistance mutations in HIV-infected patients with prior experience of non-nucleoside reverse transcriptase inhibitors. J Antimicrob Chemother 2007, 60:1409–1410.

    Article  PubMed  CAS  Google Scholar 

  28. Vingerhoets J, Azijn H, Fransen E, et al.: TMC125 displays a high genetic barrier to the development of resistance: evidence from in vitro selection experiments. J Virol 2005, 79:12773–12782.

    Article  PubMed  CAS  Google Scholar 

  29. Intelence (etravirine) [package insert]. Mechelen, Belgium: Tibotec; 2008.

  30. Lazzarin A, Campbell T, Clotet B, et al.; DUET-2 Study Group: Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebocontrolled trial. Lancet 2007, 370:39–48.

    Article  PubMed  CAS  Google Scholar 

  31. Madruga JV, Cahn P, Grinsztejn B, et al.; DUET-1 Study Group: Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet 2007, 370:29–38.

    Article  PubMed  CAS  Google Scholar 

  32. Otto MJ: New nucleoside reverse transcriptase inhibitors for the treatment of HIV infections. Curr Opin Pharmacol 2004, 4:431–436.

    Article  PubMed  CAS  Google Scholar 

  33. Anderson PL, Kakuda TN, Lichtenstein KA: The cellular pharmacology of nucleoside- and nucleotide-analogue reverse transcriptase inhibitors and its relationship to clinical toxicities. Clin Infect Dis 2004, 38:743–753.

    Article  PubMed  CAS  Google Scholar 

  34. Piliero PJ: Pharmacokinetic properties of nucleoside/nucleotide reverse transcriptase inhibitors. J Acquir Immune Defic Syndr 2004, 37:S2–S12.

    Article  PubMed  CAS  Google Scholar 

  35. Ofotokun I, Acosta EP, Lennox JL, et al.: Antiretroviral pharmacokinetic profile: a review of sex differences. Gend Med 2007, 47:106–119.

    Article  Google Scholar 

  36. Marier JF, Dimarco M, Guilbaud R, et al.: Pharmacokinetics of lamivudine, zidovudine, and nevirapine administered as a fixed-dose combination formulation versus coadministration of the individual products. J Clin Pharmacol 2007, 47:1381–1389.

    Article  PubMed  CAS  Google Scholar 

  37. Gallant JE, DeJesus E, Arribas JR, et al.: Tenofovir DF, emtricitabine, and efavirenz vs zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med 2006, 354:251–260.

    Article  PubMed  CAS  Google Scholar 

  38. Markowitz M, Morales-Ramirez JO, Nguyen BY, et al.: Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals. J Acquir Immune Defic Syndr 2006, 43:509–515.

    Article  PubMed  CAS  Google Scholar 

  39. Iwamoto M, Wenning LA, Petry AS, et al.: Safety, tolerability, and pharmacokinetics of raltegravir after single and multiple doses in healthy subjects. Clin Pharmacol Ther 2008, 83:293–299.

    Article  PubMed  CAS  Google Scholar 

  40. Isentress (raltegravir) tablets [package insert]. Whitehouse Station, NJ: Merck & Co.; 2007.

  41. Kassahun K, McIntosh I, Cui D, et al.: Metabolism and disposition in humans of raltegravir (MK-0518), an anti-AIDS drug targeting the human immunodeficiency virus 1 integrase enzyme. Drug Metab Dispos 2007, 35:1657–1663.

    Article  PubMed  CAS  Google Scholar 

  42. Levin J: Raltegravir FDA safety report 2007. Available at http://www.natap.org/2007/HIV/083107_07.htm. Accessed March 2008.

  43. Grinsztejn B, Nguyen BY, Katlama C, et al.: Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet 2007, 369:1261–1269.

    Article  PubMed  CAS  Google Scholar 

  44. Murray JM, Emery S, Kelleher AD, et al.: Antiretroviral therapy with the integrase inhibitor raltegravir alters decay kinetics of HIV, significantly reducing the second phase. AIDS 2007, 21:2315–2321.

    PubMed  CAS  Google Scholar 

  45. Briz V, Poveda E, Soriano V: HIV entry inhibitors: mechanisms of action and resistance pathways. J Antimicrob Chemother 2006, 57:619–627.

    Article  PubMed  CAS  Google Scholar 

  46. Lalezari JP, Eron JJ, Carlson M, et al.: A phase II clinical study of the long-term safety and antiviral activity of enfuvirtide-based antiretroviral therapy. AIDS 2003, 17:691–698.

    Article  PubMed  CAS  Google Scholar 

  47. Dorr P, Westby M, Dobbs S, et al.: Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents Chemother 2005, 49:4721–4732.

    Article  PubMed  CAS  Google Scholar 

  48. Lorenzen T, Stoehr A, Walther I, Plettenberg A: CCR5 antagonists in the treatment of treatment-experienced patients infected with CCR5 tropic HIV-1. Eur J Med Res 2007, 12:419–425.

    PubMed  CAS  Google Scholar 

  49. Carter NJ, Keating GM: Maraviroc. Drugs 2007, 67:2277–2288.

    Article  PubMed  CAS  Google Scholar 

  50. Selzentry (maraviroc) tablets [package insert]. New York: Pfizer; 2007.

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Authors and Affiliations

  1. School of Medicine, Division of Clinical Pharmacology, University of Alabama at Birmingham, 1530 Third Avenue South, VH 116, Birmingham, AL, 35294, USA

    Edward P. Acosta

Authors
  1. Mary C. Long
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  2. Jennifer R. King
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  3. Edward P. Acosta
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Correspondence to Edward P. Acosta.

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Long, M.C., King, J.R. & Acosta, E.P. Pharmacologic aspects of new antiretroviral drugs. Curr HIV/AIDS Rep 6, 43–50 (2009). https://doi.org/10.1007/s11904-009-0007-y

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