A Review of the Pharmacokinetics of Abacavir

Abstract

Abacavir is a carbocyclic 2′-deoxyguanosine nucleoside reverse transcriptase inhibitor that is used as either a 600-mg once-daily or 300-mg twice-daily regimen exclusively in the treatment of HIV infection. Abacavir is rapidly absorbed after oral administration, with peak concentrations occurring 0.63–1 hour after dosing. The absolute bioavailability of abacavir is approximately 83%. Abacavir pharmacokinetics are linear and doseproportional over the range of 300–1200 mg/day. To date, one study has assessed the steady-state pharmaco-kinetics of abacavir following a 600-mg once-daily regimen, and reported a geometric mean steady-state abacavir peak concentration of 3.85 µg/mL. Although this concentration is higher than the steady-state abacavir peak concentration reported following a 300-mg twice-daily regimen (0.88–3.19 µg/mL, depending on the study), the geometric mean steady-state abacavir exposure over 24 hours was similar following these regimens. Coadministration with food has no significant effect on abacavir exposure; therefore, abacavir may be administered with or without food.

The apparent volume of distribution of abacavir after intravenous administration is approximately 0.86 ± 0.15 L/kg, suggesting that abacavir is distributed to extravascular spaces. Binding to plasma proteins is about 50% and is independent of the plasma abacavir concentration.

Abacavir is extensively metabolized by the liver; less than 2% is excreted as unchanged drug in the urine. Abacavir is primarily metabolized via two pathways, uridine diphosphate glucuronyltransferase and alcohol dehydrogenase, resulting in the inactive glucuronide metabolite (361W94, ∼36% of the dose recovered in the urine) and the inactive carboxylate metabolite (2269W93, ∼30% of the dose recovered in the urine). The remaining 15% of abacavir equivalents found in the urine are minor metabolites, each less than 2% of the total dose. Faecal elimination accounts for about 16% of the dose. The terminal elimination half-life of abacavir is approximately 1.5 hours. The antiviral effect of abacavir is due to its intracellular anabolite, carbovir-triphosphate (CBV-TP). When assessed by validated high-performance liquid chromatography electrospray ionization tandem mass spectrometry, CBV-TP has been shown to have a long elimination half-life (>20 hours), supporting once-daily dosing. The mean CBV-TP trough concentrations do not differ following abacavir 600-mg once-daily and 300-mg twice-daily regimens.

Limited data are available for abacavir in subjects with renal dysfunction or hepatic impairment. Abacavir pharmacokinetics in HIV-infected subjects with end-stage renal disease were found to be no different from those observed in healthy adults; this finding was consistent with the kidney being a minor route of abacavir elimination. A study of abacavir pharmacokinetics in hepatically impaired adults (Child-Pugh score of 5–6) showed that the abacavir area under the plasma concentration-time curve and elimination half-life were 89% and 58% greater, respectively, suggesting that the daily dose of abacavir should be reduced in patients with mild hepatic impairment (Child-Pugh score of 5–6). Abacavir pharmacokinetics have not been studied in patients with higher Child-Pugh scores.

Abacavir is not significantly metabolized by cytochrome P450 (CYP) enzymes, nor does it inhibit these enzymes. Therefore, clinically significant drug interactions between abacavir and drugs metabolized by CYP enzymes are unlikely. The potential for drug interactions is no different when abacavir is used as a once-daily regimen versus a twice-daily regimen. No clinically significant drug interactions have been observed between recommended doses of abacavir and lamivudine, zidovudine, alcohol (ethanol) or methadone.

This is a preview of subscription content, access via your institution.

Fig. 1
Table I
Fig. 2
Table II
Fig. 3
Fig. 4
Fig. 5
Table III
Table IV
Fig. 6
Table V

Notes

  1. 1.

    The use of trade names is for product identification purposes only and does not imply endorsement.

References

  1. 1.

    Deeks SG, Wrin T, Liegler T, et al. Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia. N Engl J Med 2001; 344: 472–80

    PubMed  CAS  Article  Google Scholar 

  2. 2.

    Lawrence J, Mayers DL, Hullsiek KH, et al. Structured treatment interruption in patients with multidrug-resistant human immunodeficiency virus. N Engl J Med 2003; 349: 837–46

    PubMed  Article  Google Scholar 

  3. 3.

    Mocroft A, Ledergerber B, Katlama C, et al. Decline in the AIDS and death rates in the EuroSIDA study: an observational study. Lancet 2003; 362: 22–9

    PubMed  CAS  Article  Google Scholar 

  4. 4.

    Gandhi T, Wei W, Amin K, et al. Effect of maintaining highly active antiretroviral therapy on AIDS events among patients with late-stage HIV infection and inadequate response to therapy. Clin Infect Dis 2006; 42: 878–84

    PubMed  Article  Google Scholar 

  5. 5.

    Valdez H, Chowdhry TK, Asaad R, et al. Changing spectrum of mortality due to human immunodeficiency virus: analysis of 260 deaths during 1995–1999. Clin Infect Dis 2001; 32: 1487–93

    PubMed  CAS  Article  Google Scholar 

  6. 6.

    Conway B. The role of adherence to antiretroviral therapy in the management of HIV infection. J Acquir Immune Def Syndr 2007; 45 Suppl. 1: S14–8

    CAS  Google Scholar 

  7. 7.

    Bangsberg DR. Monitoring adherence to HIV antiretroviral therapy in routine clinical practice: the past, the present, and the future. AIDS Behav 2006; 10: 249–51

    PubMed  Article  Google Scholar 

  8. 8.

    Bangsberg DR, Perry S, Charlebois ED, et al. Non-adherence to highly active antiretroviral therapy predicts progression to AIDS. AIDS 2001; 15: 1181–3

    PubMed  CAS  Article  Google Scholar 

  9. 9.

    Jordan J, Carranza Rosenzweig J, Pathak D, et al. Perceived influence of regimen characteristics on adherence [abstract/poster no. 121]. 5th International Congress on Drug Therapy in HIV Infection; 2000 Oct 22–26; Glasgow

    Google Scholar 

  10. 10.

    Gatti AM, Arpinelli F, Visconà G, et al. Impact of less complex HIV therapy on adherence and quality of life [abstract/poster no. 96]. 6th International Congress on Drug Therapy in HIV Infection; 2002 Nov 17–21; Glasgow

    Google Scholar 

  11. 11.

    Stone VE, Jordan J, Tolson J, et al. Potential impact of once daily regimens on adherence to HAART [poster no. 486]. 40th Annual Meeting of the Infectious Diseases Society of America; 2002 Oct 24–27; Chicago (IL)

    Google Scholar 

  12. 12.

    US Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the use of antiretrovi-ral agents in HIV-infected adults and adolescents [online]. Rockville (MD): DHSS, 2008 Jan 29. Available from URL: http://www.aidsinfo.nih.gov/Guide-lines/GuidelineDetail.aspx?.MenuItem=Guidelines&Search=Off&Guide-lineID=7&ClassID=1 [Accessed 2008 Mar 17]

  13. 13.

    Faletto MB, Miller WH. Garvey EP, et al. Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89. Antimicrob Agents Chemother 1997; 41: 1099–107

    PubMed  CAS  Google Scholar 

  14. 14.

    Daluge SM, Good SS, Faletto MB, et al. 1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity. Antimicrob Agents Chemother 1997 May; 41: 1082–93

    PubMed  CAS  Google Scholar 

  15. 15.

    Fischl M, Greenberg S, Clumeck N, et al. Safety and activity of abacavir (1592, ABC) with 3TC/ZDV in antiretroviral-naive subjects [abstract no. 12230]. 12th World AIDS Conference; 1998 Jun 28–Jul 3; Geneva

    Google Scholar 

  16. 16.

    Hicks C, Fischl M, Greenberg S, et al. Ziagen™ (abacavir, ABC, 1592) combined with 3TC & ZDV provides a potent & durable response through 48 weeks in HIV-1-infected antiretroviral therapy (ART)-naive adults (CNA3003) [abstract/poster no. 341]. 37th Annual Meeting of the Infectious Disease Society of America; 1999 Nov 18–20; Philadelphia (PA)

    Google Scholar 

  17. 17.

    Staszewski S, Keiser P, Montaner J, et al. Abacavir-lamivudine-zidovudine vs indinavir-lamivudine-zidovudine in antiretroviral-naive HIV-infected adults: a randomized equivalence trial. JAMA 2001; 285: 1155–63

    PubMed  CAS  Article  Google Scholar 

  18. 18.

    Matheron S, Descamps D, Boué F, et al. Triple nucleoside combination zidovudine/lamivudine/abacavir versus zidovudine/lamivudine/nelfinavir as first-line therapy in HIV-1-infected adults: a randomized trial. Antivir Ther 2003; 8: 163–71

    PubMed  CAS  Google Scholar 

  19. 19.

    Vibhagool A, Cahn P, Schlechter M, et al. Triple nucleoside treatment with abacavir plus the lamivudine/zidovudine combination tablet (COM) compared to indinavir/COM in antiretroviral therapy-naive adults: results of a 48-week open label, equivalence trial (CNA3014). Curr Med Res Opin 2004; 20: 1103–14

    PubMed  CAS  Article  Google Scholar 

  20. 20.

    Bowonwatanuwong C, Mootsikapun P, Supparatpinyo K, et al. A randomised, open-label study to investigate abacavir (ABC) and lamivudine (3TC) as once daily (qd) components of a triple combination regimen (EPV40001) [poster no. 004]. 1st International AIDS Society (IAS) Conference on HIV Pathogenesis and Treatment; 2001 Jul 8–11; Buenos Aires

    Google Scholar 

  21. 21.

    Kumar PN, Rodriguez-French A, Thompson MA, et al. A prospective, 96-week study of the impact of Trizivir®, Combivir®/nelfinavir, and lamivudine/stavu-dine/nelfinavir on lipids, metabolic parameters and efficacy in antiretroviral-naive patients: effect of sex and ethnicity. HIV Med 2006; 7: 85–98

    PubMed  CAS  Article  Google Scholar 

  22. 22.

    Gulick RM, Ribaudo H, Shikuma CM, et al. Triple nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med 2004; 350: 1850–61

    PubMed  CAS  Article  Google Scholar 

  23. 23.

    Ruane PJ, Kubota MK, Williams II AL, et al. Safety/tolerability and efficacy of abacavir-containing combination therapy in HIV-1-infected adults in a clinical practice setting: results of ZORRO. Infect Dis Clin Pract 2004; 12: 15–25

    Article  Google Scholar 

  24. 24.

    Moyle GJ, DeJesus E, Cahn P, et al. Abacavir once or twice daily combined with once-daily lamivudine and efavirenz for the treatment of antiretroviral-naive HIV-infected adults: results of the Ziagen Once Daily in Antiretroviral Combination study. J Acquir Immune Defic Syndr 2005; 38: 417–25

    PubMed  CAS  Article  Google Scholar 

  25. 25.

    DeJesus E, Herrera G, Teofilo E, et al. Abacavir versus zidovudine combined with lamivudine and efavirenz, for the treatment of antiretroviral-naive HIV-infected adults. Clin Infect Dis 2004; 39: 1038–46

    PubMed  CAS  Article  Google Scholar 

  26. 26.

    Rodriguez-French A, Boghossian J, Gray GE, et al. The NEAT study: a 48-week open-label study to compare the antiviral efficacy and safety of GW433908 versus nelfinavir in antiretroviral therapy-naive HIV-1-infected patients. J Ac-quir Immune Defic Syndr 2004; 35: 22–32

    CAS  Article  Google Scholar 

  27. 27.

    Gathe Jr JC, Ive P, Wood R, et al. SOLO: 48-week efficacy and safety comparison of once-daily fosamprenavir/ritonavir versus twice-daily nelfinavir in naive HIV-1-infected patients. AIDS 2004; 18: 1529–37

    PubMed  CAS  Article  Google Scholar 

  28. 28.

    Rodriguez A, Johnson J, Bartlett JA, et al. Efficacy and safety of switch to GW433908/ritonavir 200mg (908/r) QD in subjects initiating therapy with amprenavir/ritonavir 200mg (APV/r) QD: ESS40001 (CLASS) [poster no. TuPeB4504]. XVth International AIDS Conference; 2004 Jul 11–16; Bangkok

    Google Scholar 

  29. 29.

    Gallant JE, Rodriguez AE, Weinberg WG, et al. Early virologic nonresponse to tenofovir, abacavir, and lamivudine in HIV-infected antiretroviral-naive subjects. J Infect Dis 2005; 192: 1921–30

    PubMed  CAS  Article  Google Scholar 

  30. 30.

    Khanlou H, Yeh V, Guyer B, et al. Early virologic failure in a pilot study evaluating the efficacy of therapy containing once-daily abacavir, lamivudine, and te-nofovir DF in treatment-naive HIV-infected patients. AIDS Patient Care STDS 2005; 19: 135–40

    PubMed  Article  Google Scholar 

  31. 31.

    Landman R, Peytavin G, Descamps D, et al. Early virologic failure and rescue therapy of tenofovir, abacavir, and lamivudine for initial treatment of HIV-1 infection: TONUS study. HIV Clin Trials 2005; 6: 291–301

    PubMed  CAS  Article  Google Scholar 

  32. 32.

    Jemsek J, Hutcherson P, Harper E. Poor virologic responses and early emergence of resistance in treatment naive, HIV-infected patients receiving a once daily triple nucleoside regimen of didanosine, lamivudine and tenofovir DF [abstract no. 51]. 11th Conference on Retroviruses and Opportunistic Infections; 2004 Feb 8–11; San Francisco (CA)

    Google Scholar 

  33. 33.

    Gilliam BL, Sajadi MM, Amoroso A, et al. Tenofovir and abacavir combination therapy: lessons learned from an urban clinic population. AIDS Patient Care and STDs 2007; 21: 240–6

    PubMed  Article  Google Scholar 

  34. 34.

    Mastrioianni CM, d’Ettorre G, Vullo V. Evolving simplified treatment strategies for HIV infection: the role of a single-class quadruple-nucleoside/nucleotide regimen of Trizivir® and tenofovir. Expert Opin Pharmacother 2006; 7: 2233–41

    Article  Google Scholar 

  35. 35.

    Ray AS, Myrick F, Vela JE, et al. Lack of a metabolic and antiviral drug interaction between tenofovir, abacavir and lamivudine. Antivir Ther 2005; 10: 451–7

    PubMed  CAS  Google Scholar 

  36. 36.

    Hawkins T, Veikley W, St Claire III RL, et al. Intracellular pharmacokinetics of tenofovir diphosphate, carbovir triphosphate, and lamivudine triphosphate in patients receiving triple-nucleoside regimens. J Acquir Immune Defic Syndr 2005; 39: 406–11

    PubMed  CAS  Article  Google Scholar 

  37. 37.

    Moyle G, Higgs C, Teague A, et al. An open-label, randomized comparative pilot study of a single-class quadruple therapy regimen versus a 2-class triple therapy regimen for individuals initiating antiretroviral therapy. Antivir Ther 2006; 11: 73–8

    PubMed  CAS  Google Scholar 

  38. 38.

    Greiger-Zanlungo P, Rubin D, Glick G, et al. Quadruple nucleoside reverse transcriptase inhibitor (NRTI) therapy with Trizivir (TZV) and Viread (TDF) in HAART-naive and -experienced HIV/AIDS patients [abstract no. TuPeB4513]. 15th International AIDS Conference; 2004 Jul 11–16; Bangkok

    Google Scholar 

  39. 39.

    Latham V, Stebbing J, Mandalia S, et al. Adherence to Trizivir and tenofovir as a simplified salvage regimen is associated with suppression of viraemia and a decreased cholesterol. J Antimicrob Chemother 2005; 56: 186–9

    PubMed  CAS  Article  Google Scholar 

  40. 40.

    Rodriguez A, Hill-Zabala C, Sloan L, et al. Patients experiencing early virologic failure on a protease inhibitor- or nonnucleoside reverse transcriptase inhibitor-based initial regimen containing a thymidine analogue and lamivudine can be successfully treated with a quadruple-nucleoside regimen [letter]. J Acquir Immune Defic Syndr 2006; 41: 127–9

    PubMed  Article  Google Scholar 

  41. 41.

    Ruane P, Luber A, Gaultier C, et al. Efficacy of Trizivir (TZV) and tenofovir (TDF) as HAART for HIV infected patients with current or underlying reverse transcriptase (RT) resistance [abstract no. TuPeB4600]. XVth International AIDS Conference; 2004 Jul 24–27; Rio de Janeiro

    Google Scholar 

  42. 42.

    Dauer B, Stuermer M, Mueller A, et al. Virologic response to tenofovir DF (TDF) plus Trizivir (TZV) therapy in heavily antiretroviral (ART-experienced, HIV+ patients: 24-week results [abstract/poster no. H-520]. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2005 Dec 16–19; Washington, DC

    Google Scholar 

  43. 43.

    Khanlou H, Guyer B, Farthing C. Efficacy of tenofovir as intensification of zidovudine/lamivudine/abacavir fixed-dose combination in the treatment of HIV-positive patients. J Acquir Immune Defic Syndr 2005; 38: 627–8

    PubMed  Article  Google Scholar 

  44. 44.

    D’Ettorre, Mastroianni CM, Massetti AP, et al. Switching from protease inhibitors to a single-class regimen of abacavir/lamivudine/zidovudine plus tenofovir in patients with HIV load suppression [letter]. AIDS 2005; 19: 841–6

    PubMed  Article  Google Scholar 

  45. 45.

    Parikh UM, Bacheler L, Koontz DL, et al. The K65R mutation in human immunodeficiency virus type 1 reverse transcriptase exhibits bidirectional phenotypic antagonism with thymidine analog mutations. J Virol 2006; 80: 4971–7

    PubMed  CAS  Article  Google Scholar 

  46. 46.

    Katlama C, Fenske S, Gazzard B, et al. TRIZAL study: switching from successful HAART to Trizivir™ (abacavir-lamivudine-zidovudine combination tablet): 48 weeks efficacy, safety and adherence results. HIV Med 2003; 4: 79–86

    PubMed  CAS  Article  Google Scholar 

  47. 47.

    Lafeuillade A, Clumeck N, Mallolas J, et al. Comparison of metabolic abnormalities and clinical lipodystrophy 48 weeks after switching from HAART to Trizivir versus continued HAART: the Trizal study. HIV Clin Trials 2003; 4: 37–43

    PubMed  Article  Google Scholar 

  48. 48.

    Keiser PH, Sension MG, DeJesus E, et al. Substituting abacavir for hyperlipidemia-associated protease inhibitors in HAART regimens improves fasting lipid profiles, maintains virologic suppression, and simplifies treatment. BMC Infect Dis 2005; 5(2): 1–15

    Google Scholar 

  49. 49.

    Clumeck N, Goebel F, Rozenbaum W, et al. Simplification with abacavir-based triple nucleoside therapy versus continued protease inhibitor-based highly active antiretroviral therapy in HIV-1-infected patients with undetectable plasma HIV-1 RNA. AIDS 2001; 15: 1517–26

    PubMed  CAS  Article  Google Scholar 

  50. 50.

    Martinez E, Anaiz JA, Podzamczer D, et al. Substitution of nevirapine, efavirenz, or abacavir for protease inhibitors in patients with human immunodeficiency virus infection. N Engl J Med 2003; 349: 1036–46

    PubMed  CAS  Article  Google Scholar 

  51. 51.

    Opravil M, Hirschel B, Lazzarin A, et al. A randomized trial of simplified maintenance therapy with abacavir, lamivudine, and zidovudine in human immunodeficiency virus infection. J Infect Dis 2002; 185: 1251–60

    PubMed  CAS  Article  Google Scholar 

  52. 52.

    Maggiolo F, Ripamonti D, Ravasio L, et al. Outcome of 2 simplification strategies for the treatment of human immunodeficiency virus type 1 infection. Clin Infect Dis 2003; 37: 41–9

    PubMed  Article  Google Scholar 

  53. 53.

    Kakuda TN. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clin Ther 2000; 22: 685–708

    PubMed  CAS  Article  Google Scholar 

  54. 54.

    de Truchis P, Force G, Welker Y, et al. Efficacy and safety of a quadruple combination Combivir + abacavir + efavirenz regimen in antiretroviral treatment-naive HIV-1-infected adults: La Francilienne. J Acquir Immune Defic Syndr 2002; 31: 178–82

    PubMed  Article  Google Scholar 

  55. 55.

    John M, McKinnon EJ, James IR, et al. Randomised, controlled, 48-week study of switching stavudine and/or protease inhibitors to combivir/abacavir to prevent or reverse lipoatrophy in HIV-infected patients. J Acquir Immune Defic Syndr 2003; 33: 29–33

    PubMed  CAS  Article  Google Scholar 

  56. 56.

    Matheron S, Livrozet JM, Boué F, et al. Long-term safety and efficacy of two antiretroviral therapies: Combivir™ + abacavir vs Combivir™ + nelfinavir − ECUREUIL 2 (CNAF3021) [abstract/poster no. 556]. 2nd IAS Conference on HIV Pathogenesis and Treatment; 2003 Jul 13–16; Paris

    Google Scholar 

  57. 57.

    Stone C, Ait-Khaled M, Tortell S, et al. Long term (84–120 weeks) virologic and genotypic data following treatment with abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) [poster no. 17]. 2nd Frankfurt Symposium on the Clinical Implications of HIV Drug Resistance; 2000 Feb 26–27; Frankfurt

    Google Scholar 

  58. 58.

    Rawlings MK, Thompson MA, Farthing CF, et al. Impact of an educational program on efficacy and adherence with a twice-daily lamivudine/zidovudine/abacavir regimen in underrepresented HIV-infected patients. J Acquir Immune Defic Syndr 2003; 34: 174–83

    PubMed  Article  Google Scholar 

  59. 59.

    Hetherington S, McGuirk S, Powell G, et al. Hypersensitivity reactions during therapy with the nucleoside reverse transcriptase inhibitor abacavir. Clin Ther 2001; 23: 1603–14

    PubMed  CAS  Article  Google Scholar 

  60. 60.

    Cutrell AG, Curtis LL, Brothers CH, et al. Updated clinical characteristics and clinical risk factor analysis for suspected hypersensitivity (HSR) to abacavir (ABC) comparing ABC once daily (QD) vs ABC twice daily (BID) [abstract/poster no. P77]. 9th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV; 2007 Jul 19–21; Sydney

    Google Scholar 

  61. 61.

    Martin AM, Nolan D, Gaudieri S, et al. Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant. Proc Natl Acad Sci USA 2004; 101: 4180–5

    PubMed  CAS  Article  Google Scholar 

  62. 62.

    Mallal S, Nolan D, Witt C, et al. Association between the presence of HLAB*5701, HLA-DR7 and HLA-DQ3 and hypersensitivity to HIV-1 reverse transcriptase inhibitor abacavir. Lancet 2002; 359: 727–32

    PubMed  CAS  Article  Google Scholar 

  63. 63.

    Hughes A, Mosteller M, Bansal A, et al. Association of genetic variants in HLA-B region with hypersensitivity to abacavir in some, but not all, populations. Pharmacogenomics 2004; 5: 203–11

    PubMed  CAS  Article  Google Scholar 

  64. 64.

    Waters L, Gritz A, Maitland D, et al. HLA-B5701 testing and abacavir hypersensitivity: a single-center experience [abstract no. PL9.2]. 8th International Congress on Drug Therapy in HIV Infection; 2006 Nov 12–16; Glasgow

    Google Scholar 

  65. 65.

    Zucman D, De Truchis P, Majerholc C, et al. Screening for HLA B5701 in a population of HIV patients of diverse ethnic origin exposed to abacavir in France [abstract no. P116]. 8th International Congress on Drug Therapy in HIV Infection; 2006 Nov 12–16; Glasgow

    Google Scholar 

  66. 66.

    Rodriguez-Novoa S, Garcia P, Gonzalez G, et al. Value of HLAB*5701 allele to predict abacavir hypersensitivity in Spaniards [abstract no. P117]. 8th International Congress on Drug Therapy in HIV Infection; 2006 Nov 12–16; Glasgow

    Google Scholar 

  67. 67.

    Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 2008; 358: 568–79

    PubMed  Article  Google Scholar 

  68. 68.

    Hervey PS. Perry CM. Abacavir: a review of its clinical potential in patients with HIV infection. Drugs 2000; 60: 447–79

    PubMed  CAS  Article  Google Scholar 

  69. 69.

    Porche D. Abacavir. J Assoc Nurses AIDS Care 2000; 11: 88–90

    Google Scholar 

  70. 70.

    Dando TM, Scott LJ. Abacavir plus lamivudine: a review of their combined use in the management of HIV infection. Drugs 2005; 65: 285–302

    PubMed  CAS  Article  Google Scholar 

  71. 71.

    Keiser P, Nassar N. Trizivir. Expert Opin Pharmacother 2003; 3: 619–24

    Google Scholar 

  72. 72.

    Porche D. Abacavir sulfate, lamivudine, zidovudine (Trizivir™). J Assoc Nurses AIDS Care 2001; 12: 88–90

    PubMed  CAS  Article  Google Scholar 

  73. 73.

    Ibbotson T, Perry CM. Lamivudine/zidovudine/abacavir triple combination tablet. Drugs 2003; 63: 1089–98

    PubMed  CAS  Article  Google Scholar 

  74. 74.

    Chittick GE, Gillotin C, McDowell JA, et al. Abacavir: absolute bioavailability, bioequivalence of three oral formulations, and effect of food. Pharmacotherapy 1999 Aug; 19: 932–42

    PubMed  CAS  Article  Google Scholar 

  75. 75.

    Kumar PN, Sweet DE, McDowell JA, et al. Safety and pharmacokinetics of abacavir (1592U89) following oral administration of escalating single doses in human immunodeficiency virus type I-infected adults. Antimicrob Agents Chemother 1999; 43: 603–8

    PubMed  CAS  Google Scholar 

  76. 76.

    Weller S, Radomski KM, Lou Y, et al. Population pharmacokinetics and pharmacodynamic modeling of abacavir (1592U89) from a dose-ranging double-blind, randomized monotherapy trial with human immunodeficiency virus-infected subjects. Antimicrob Agents Chemother 2000; 44: 2052–60

    PubMed  CAS  Article  Google Scholar 

  77. 77.

    McDowell JA, Chittick GE, Ravitch JR, et al. Pharmacokinetics of [14C] abacavir, a human immunodeficiency virus type I (HIV-1) reverse transcriptase inhibitor, administered in a single oral dose to HIV-infected adults: a mass balance study. Antimicrob Agents Chemother 1999; 43: 2855–61

    PubMed  CAS  Google Scholar 

  78. 78.

    Wang LH, Chittick GE, McDowell JA. Single-dose pharmacokinetics and safety of abacavir (1592U89), zidovudine, and lamivudine administered alone and in combination in adults with human immunodeficiency virus infection. An-timicrob Agents Chemother 1999; 43: 1708–15

    CAS  Google Scholar 

  79. 79.

    Yuen GJ, Lou Y, Thompson NF, et al. Abacavir/lamivudine/zidovudine as a combined formulation tablet: bioequivalence compared with each component administered concurrently and the effect of food on absorption. J Clin Pharmacol 2001; 41: 277–88

    PubMed  CAS  Article  Google Scholar 

  80. 80.

    Baker KL, Lou Y, Yuen G, Murray S, Stein D. The bioequivalence and effect of food on a new once-a-day fixed-dose combination tablet of abacavir (ABC) and lamivudine (3TC) [abstract/poster no. A-458]. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2004 Oct 30–Nov 2; Washington, DC

    Google Scholar 

  81. 81.

    van Praag RME, van Weert ECM, van Heeswijk RPG, et al. Stable concentrations of zidovudine, stavudine, lamivudine, abacavir, and nevirapine in serum and cerebrospinal fluid during 2 years of therapy. Antimicrob Agents Chemother 2002; 46: 896–9

    PubMed  Article  CAS  Google Scholar 

  82. 82.

    Crémieux A-C, Katlama C, Gillotin C, et al. A comparison of the steady-state pharmacokinetics and safety of abacavir, lamivudine, and zidovudine taken as a triple combination tablet and as abacavir plus a lamivudine-zidovudine double combination tablet by HIV-1-infected adults. Pharmacotherapy 2001; 21: 424–30

    PubMed  Article  Google Scholar 

  83. 83.

    DiCenzo R, Forrest A, Squires KE, et al. Indinavir, efavirenz, and abacavir pharmacokinetics in human immunodeficiency virus-infected subjects. An-timicrob Agents Chemother 2003; 47: 1929–35

    CAS  Article  Google Scholar 

  84. 84.

    Piliero P, Shachoy-Clark A, Para M, et al. A study examining the pharmacokinetics of abacavir and the intracellular carbovir triphosphate (GSK protocol no. CNA10905) [abstract no. A-1797]. 43rd International Conference on Antimicrobial Agents and Chemotherapy; 2003 Sep 14–17; Chicago (IL)

    Google Scholar 

  85. 85.

    McDowell JA, Lou Y, Symonds WS, et al. Multiple-dose pharmacokinetics and pharmacdynamics of abacavir alone and in combination with zidovudine in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother 2000; 44: 2061–7

    PubMed  CAS  Article  Google Scholar 

  86. 86.

    Hughes W, McDowell JA, Shenep J, et al. Safety and single-dose pharmacokinetics of abacavir (1592U89) in human immunodeficiency virus type 1-infected children. Antimicrob Agents Chemother 1999; 43: 609–15

    PubMed  CAS  Google Scholar 

  87. 87.

    Bergshoeff A, Burger D, Verweij C, et al. Plasma pharmacokinetics of once- versus twice-daily lamivudine and abacavir: simplification of combination treatment in HIV-1-infected children (PENTA-13). Antivir Ther 2005; 10: 239–46

    PubMed  CAS  Google Scholar 

  88. 88.

    Johnson GM, Rodman JH, McDowell J, et al. Preliminary analysis of abacavir succinate (ABC) pharmacokinetics in neonates differs from adults and young children [abstract no. 720]. 7th Conference on Retroviruses and Opportunistic Infections; 2000 Jan 30–Feb 2; San Francisco (CA)

    Google Scholar 

  89. 89.

    Best BM, Mirochnick M, Capparelli EV, et al. Impact of pregnancy on abacavir pharmacokinetics. AIDS 2006; 20: 553–60

    PubMed  CAS  Article  Google Scholar 

  90. 90.

    Chappuy H, Tréluyer J-M, Julien V, et al. Maternal-fetal transfer and amniotic fluid accumulation of nucleoside analogue reverse transcriptase inhibitors in human immunodeficiency virus-infected pregnant women. Antimicrob Agents Chemother 2004; 48: 4332–6

    PubMed  CAS  Article  Google Scholar 

  91. 91.

    Data on file, GlaxoSmithKline, 2008

  92. 92.

    Izzedine H, Launay-Vacher V, Aymard G, et al. Pharmacokinetics of abacavir in HIV-1-infected patients with impaired renal function. Nephron 2001; 89: 62–7

    PubMed  CAS  Article  Google Scholar 

  93. 93.

    Thompson M, Torres G, Enstrom T, et al. Single-dose plasma profiles of abacavir (ABC, 1592) in HIV-1-infected individuals with renal failure [abstract/poster no. 42278]. 12th World AIDS Conference; 1998 Jun 28–Jul 3; Geneva

    Google Scholar 

  94. 94.

    Moyle G, Fletcher C, Higgs C, et al. An open-label, two-period, crossover, pharmacokinetic (PK) study of abacavir (ABC) and its intracellular anabolite carbovir triphosphate (CBV-TP) following 600mg once-daily (QD) and 300mg twice-daily (BD) administration of abacvir in HIV-infected subjects [abstract/poster no. WEPEB002]. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; 2007 Jul 22–25; Sydney

    Google Scholar 

  95. 95.

    Capparelli EV, Letendre SL, Ellis RJ, et al. Population pharmacokinetics of abacavir in plasma and cerebrospinal fluid. Antimicrob Agents Chemother 2005; 49: 2504–6

    PubMed  CAS  Article  Google Scholar 

  96. 96.

    Price RW, Aweeka F, Bellibas SE, et al. Pharmacokinetics of abacavir (1592U89) in cerebrospinal fluid (CSF) using multiple lumbar punctures of few subjects and ’sparse sampling’ techniques [abstract no. 42271]. 12th World AIDS Conference; 1998 Jun 28–Jul 3; Geneva

    Google Scholar 

  97. 97.

    Portegies P. The CNS as a sanctuary site for HIV: implications for antiretroviral therapy [abstract]. Satellite symposium of the 6th European Conference on Clinical Aspects and Treatment of HIV Infection: Meeting Today’s Challenges in HIV Therapy; 1997 Oct 11–15; Hamburg

    Google Scholar 

  98. 98.

    Coates JAV, Cammack N, Jenkinson HJ, et al. (s-)-2′-deoxy-3′-thiacytidine is a potent, highly selective inhibitor of human immunodeficiency virus type 1 and type 2 replication in vitro. Antimicrob Agents Chemother 1992; 36: 733–9

    PubMed  CAS  Article  Google Scholar 

  99. 99.

    Lea AP, Faulds D. Stavudine: a review of its pharmacodynamic and pharmacokinetic properties and clinical potential in HIV Infection. Drugs 1996; 51: 846–64

    PubMed  CAS  Article  Google Scholar 

  100. 100.

    Schmid P, Conrad A, Syndulko K, et al. Quantifying HIV-1 proviral DNA using the polymerase chain reaction on cerebrospinal fluid and blood of seropositive individuals with and without neurologic abnormalities. J Acquir Immune Defic Syndr 1994; 7: 777–88

    PubMed  CAS  Google Scholar 

  101. 101.

    Ravitch JR, Jarrett JL, Robertson White H, et al. CNS penetration of the antiretroviral 1592 in human and animal models [abstract no. 636]. 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5; Chicago (IL)

    Google Scholar 

  102. 102.

    Ravitch JR, Walsh JS, Reese MJ, et al. In vitro studies of the potential for drug interactions involving the antiretroviral abacavir (1592) in humans [abstract no. 634]. 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5; Chicago (IL)

    Google Scholar 

  103. 103.

    Zimmerman TP, Mahony WB, Domin BA, et al. Membrane permeation characteristics of the structurally related anti-HIV agents 1592U89 and (−)-carbovir in human erythrocytes and human T-lymphoblastoid CD4+ CEM cells [abstract no. 109]. Antiviral Res 1995 Mar; 26: A283

    Google Scholar 

  104. 104.

    Kewn S, Maher B, Hoggard PG, et al. The pharmacokinetics of abacavir phospho-rylation in peripheral blood mononuclear cells from HIV+ patients [abstract no. 276A]. 5th International Congress on Drug Therapy in HIV Infection; 2000 Oct 22–26; Glasgow

    Google Scholar 

  105. 105.

    Harris M, Back D, Kewn S, et al. Intracellular carbovir triphosphate levels in patients taking abacavir once a day. AIDS 2002; 16: 1196–7

    PubMed  Article  Google Scholar 

  106. 106.

    Stocker H, Kruse G, Weber C, et al. Intracellular concentrations of 3TC-triphos-phate, carbovir-triphosphate and tenofovir-diphosphate remain stable throughout 36 weeks and NRTI treatment interrupted by NRTI free treatment periods in patients with multiresistant HIV [abstract/poster no. WePe3.2C04]. 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment; 2005 Jul 24–27; Rio de Janeiro

    Google Scholar 

  107. 107.

    Jullien V, Tréluyer J-M, Chappuy H, et al. Weight related differences in the pharmacokinetics of abacavir in HIV-infected patients. Br J Clin Pharmacol 2004; 59: 183–8

    Article  CAS  Google Scholar 

  108. 108.

    Kline MW, Blanchard S, Fletcher CV, et al. A phase I study of abacavir (1592U89) alone and in combination with other antiretroviral agents in infants and children with human immunodeficiency virus infection. AIDS Clinical Trials Group 330 Team. Pediatrics 1999; 103: e47

    PubMed  CAS  Article  Google Scholar 

  109. 109.

    Jullien V, Urien S, Chappuy H, et al. Abacavir pharmacokinetics in human immunodeficiency virus-infected children ranging in age from 1 month to 16 years: a population analysis. J Clin Pharmacol 2005; 45: 257–64

    PubMed  CAS  Article  Google Scholar 

  110. 110.

    Drusano GL, Bilello JA, Symonds WT, et al. Pharmacodynamics of abacavir in an in vitro hollow fiber model system. Antimicrob Agents Chemother 2002; 46: 464–70

    PubMed  CAS  Article  Google Scholar 

  111. 111.

    Back DJ, Khoo SH, Maher B, et al. Current uses and future hopes for clinical pharmacology in the management of HIV infection. HIV Med 2000; 1 Suppl. 2: 12–7

    PubMed  CAS  Article  Google Scholar 

  112. 112.

    Scott T, Gerondelis P, Brothers C. Intracellular inhibitory quotients (IQs) for abacavir and tenofovir-abacavir has a higher IQ [poster no. 1.7]. 6th International Workshop on Clinical Pharmacology of HIV Therapy; 2005 Apr 28–30; Quebec City

    Google Scholar 

  113. 113.

    Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients. JAMA 2004; 292: 191–201

    PubMed  CAS  Article  Google Scholar 

  114. 114.

    Gallant J, Staszewski S, Pozniak A, et al. Favorable lipid and mitochondrial DNA profile for tenofovir disoproxil fumarate compared with stavudine (d4T) in combination with lamivudine and efavirenz in antiretroviral therapy naive patients: a 48-week interim analysis [abstract no. LB-2]. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy; 2002 Sep 27–30; San Diego (CA)

    Google Scholar 

  115. 115.

    Morse G, Squires K, Hammer S, et al. Abacavir (ABC) and efavirenz (EFV) pharmacokinetics in adefovir (ADV)-containing salvage regimens. 7th Conference on Retroviruses and Opportunistic Infections [abstract no. 85]; 2000 Jan 30–Feb 2; San Francisco (CA)

    Google Scholar 

  116. 116.

    Becker S, Rodriguez AE, Nadler J, et al. Plasma pharmacokinetics do not explain virologic non-response to tenofovir + abacavir/lamivudine [abstract/poster no. TuPeB4629]. XVth International AIDS Conference; 2004 Jul 11–16; Bangkok

    Google Scholar 

  117. 117.

    Kearney B, Isaacson E, Sayre J, et al. The pharmacokinetics of abacavir, a purine nucleoside analog, are not affected by tenofovir DF [abstract no. A-1615]. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy; 2003 Sep 14–17; Chicago (IL)

    Google Scholar 

  118. 118.

    Sadler BM, Gillotin C, Lou Y, et al. Pharmacokinetic and pharmacodynamic study of the human immunodeficiency virus protease inhbitor amprenavir after multiple oral dosing. Antimicrob Agents Chemother 2001; 45: 30–7

    PubMed  CAS  Article  Google Scholar 

  119. 119.

    Waters LJ, Moyle G, Bonora S, et al. Abacavir plasma pharmacokinetics in the absence and presence of atazanavir/ritonavir or lopinavir/ritonavir and vice versa in HIV-infected patients. Antivir Ther 2007; 12: 825–30

    PubMed  CAS  Google Scholar 

  120. 120.

    APTIVUS® package insert. Ridgefield (CT): Boehringer Ingelheim Pharmaceuticals, 2007

  121. 121.

    Sellers E, Lam R, McDowell J, et al. The pharmacokinetics (PK) of abacavir (ABC) and methadone (M) following co-administration: CNAA1012 [abstract no. 663]. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1999 Sep 26–29; San Francisco (CA)

    Google Scholar 

  122. 122.

    Bart PA, Rizzardi PG, Gallant S, et al. Methadone blood concentrations are decreased by the administration of abacavir plus amprenavir. Ther Drug Monit 2001; 23: 553–5

    PubMed  CAS  Article  Google Scholar 

  123. 123.

    Allison AC, Kowalski WJ, Muller CD, et al. Mechanisms of action of mycophenolic acid. Ann N Y Acad Sci 1993; 696: 63–87

    PubMed  CAS  Article  Google Scholar 

  124. 124.

    Margolis DM, Kewn S, Coull JJ, et al. The addition of mycophenolate mofetil to antiretroviral therapy including abacavir is associated with depletion of intracellular deoxyguanosine triphosphate and a decrease in plasma HIV-1 RNA. J Acquir Immune Defic Syndr 2002; 31: 45–9

    PubMed  CAS  Article  Google Scholar 

  125. 125.

    Margolis D, Heredia A, Gaywee J, et al. Abacavir and mycophenolic acid, an inhibitor of inosine monophosphate dehydrogenase, have profound and synergistic anti-HIV activity. J Acquir Immune Defic Syndr 1999; 21: 362–70

    PubMed  CAS  Google Scholar 

  126. 126.

    Heredia A, Margolis D. Oldach D, et al. Abacavir in combination with the inosine monophosphate dehydrogenase (IMPDH) inhibitor mycophenolic acid is active against multidrug-resistant HIV-1 [letter; published erratum appears in J Acquir Immune Defic Syndr 2000; 23: 105]. J Acquir Immune Defic Synd 1999; 22: 406–7

    CAS  Google Scholar 

  127. 127.

    Sankatsing SUC, Hoggard PG, Huitema ADR, et al. Effect of mycophenolate mofetil on the pharmacokinetics of antiretroviral drugs and on intracellular nucleoside triphosphate pools. Clin Pharmacokinet 2004; 43: 823–32

    PubMed  CAS  Article  Google Scholar 

  128. 128.

    Hoggard PG, Kewn S, Maherbe A, et al. Time-dependent changes in HIV nucleoside analogue phosphorylation and the effect of hydroxyurea. AIDS 2002; 16: 2439–46

    PubMed  CAS  Article  Google Scholar 

Download references

Acknowledgements

At the time that this review was written, all authors were employees of GlaxoSmithKline and received stock and stock options as part of compensation for employment at GlaxoSmithKline.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Dr Gary E. Pakes.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Yuen, G.J., Weller, S. & Pakes, G.E. A Review of the Pharmacokinetics of Abacavir. Clin Pharmacokinet 47, 351–371 (2008). https://doi.org/10.2165/00003088-200847060-00001

Download citation

Keywords

  • Lamivudine
  • Zidovudine
  • Mycophenolate Mofetil
  • Abacavir
  • Adefovir