Advertisement

Clinical Pharmacokinetics

, Volume 43, Issue 5, pp 291–310 | Cite as

Pharmacokinetic Enhancement of Protease Inhibitor Therapy

  • Jennifer R. King
  • Heather Wynn
  • Richard Brundage
  • Edward P. Acosta
Review Article

Abstract

Combination antiretroviral therapy with two or more protease inhibitors has become the standard of care in the treatment of HIV infection. Dual protein inhibitor (PI) regimens, such as lopinavir/ritonavir, are commonly used as initial PI therapy. As viral resistance increases and the development of mechanistically novel protease inhibitors decreases, clinicians turn to ritonavir-enhanced dual PI therpay to treat salvage patients. Potency of these combination regimens is increased while pill burden, food restrictions and often, side effects are decreased. These clincial advantages result from the enhancement of their pharmacological properties, including alterations in the absorption and metabolism process. Alterations in the absorption and metabolism of protease inhibitors when co-administered with a cytochrome P450 (CYP) enzyme inhibitor, such as low dose ritonavir, are reflected by impressive changes in pharmacokinetic parameters. For example, the addition of ritonavir 100 or 200mg to saquinavir 1200–1800mg has been shown to increase saquinavir area under the concentration-time curve (AUC) by approximately 300–800% compared with saquinavir alone. The ability of ritonavir to increase plasma trough concentrations (Cmin) of concomitantly administered PIs is perhaps the greatest clinical benefit of dual or ritonavir-enhanced dual PI therapy since inadequate concentrations of antiretrovirals may support long term antiretroviral resistance. For example, lopinavir 400mg alone in healthy volunteers produced plasma concentrations that briefly exceeded the concentration required to inhibit 50% of viral replication (IC50). Yet, when low doses of ritonavir were added, Cmin values were 50- to 100-fold greater than the concentration required to produce 50% of the maximum effect for wild-type HIV (EC50). The following manuscript will discuss the rationale for combining protease inhibitors and will review pertinent pharmacokinetic and clinical data on these combination regimens.

Keywords

Ritonavir Efavirenz Indinavir Saquinavir Nelfinavir 
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

Acknowledgements

This review was supported in part by grants UO1 AI-32775 and UO1 AI-41089 from the National Institutes of Allergy and Infectious Diseases, and NIH AI 27661 and the University of Minnesota International Center for Antiviral Research and Epidemiology. The authors have provided no information on conflicts of interest directly relevant to the content of this review.

References

  1. 1.
    Acosta EP, Kakuda TN, Brundage RC, et al. Pharmacodynamics of HIV-1 protease inhibitors. Clin Infect Dis 2000; 30: S151–9PubMedCrossRefGoogle Scholar
  2. 2.
    Durant J, Clevenbergh P, Garraffo R, et al. Importance of protease inhibitor plasma levels in HIV-infected patients treated with genotypic-guided therapy: pharmacological data from the VIRADAPT study. AIDS 2000; 14: 1333–9PubMedCrossRefGoogle Scholar
  3. 3.
    Eagling VA, Back DJ, Barry MG. Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir. Br J Clin Pharmacol 1997; 44(2): 190–4PubMedCrossRefGoogle Scholar
  4. 4.
    Koudriakova T, Latsimirskaia E, Utkin I, et al. Metabolism of the human immunodeficiency virus protease inhibitors indinavir and ritonavir by human intestinal microsomes and expressed cytochrome P4503A4/3A5: mechanism-based inactivation of cytochrome P4503A by ritonavir. Drug Metab Dispos 1998; 26(6): 552–61PubMedGoogle Scholar
  5. 5.
    Barry M, Gibbons S, Back D, et al. Protease inhibitors in patients with HIV disease: clinically important pharmacokinetic considerations. Clin Pharmacokinet 1997; 32(3): 194–209PubMedCrossRefGoogle Scholar
  6. 6.
    Gatmaitan ZC, Arias IM. Structure and function of P-glycoprotein in normal liver and small intestine. Adv Pharmacol 1993; 24: 77–97PubMedCrossRefGoogle Scholar
  7. 7.
    Barry M, Mulcahy F, Merry C, et al. Pharmacokinetics and potential interactions amongst antiretroviral agents used to treat patients with HIV infection. Clin Pharmcokinet 1999; 36: 289–304CrossRefGoogle Scholar
  8. 8.
    Lillibridge JH, Liang BH, Kerr BM, et al. Characterization of the selectivity and mechanism of human cytochrome P450 inhibition by the human immunodeficiency virus-protease inhibitor nelfinavir mesylate. Drug Metab Dispos 1998; 26(7): 609–16PubMedGoogle Scholar
  9. 9.
    Kilby JM, Sfakianos G, Gizzi N, et al. Safety and pharmacokinetics of once-daily regimens of soft-gel capsule saquinavir plus minidose ritonavir in human immunodeficiency virus-negative adults. Antimicrob Agents Chemother 2000; 44(10): 2672–8PubMedCrossRefGoogle Scholar
  10. 10.
    Sham H, Kempf DJ, Molla A, et al. ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrob Agents Chemother 1998; 42(12): 3218–24PubMedGoogle Scholar
  11. 11.
    Bertz R, Lam W, Brun S, et al. Multiple dose pharmacokinetics (PK) of ABT-378/ritonavir (ABT-378/r) in HIV+ subjects [abstract 327]. Program and abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1999 Sep 26–29; San Francisco. Washington, DC: American Society for Microbiology, 1999Google Scholar
  12. 12.
    Saag MS, Kilby M, Ehrensing E, et al. Saquinavir systemic exposure and safety of once daily administration of Fortovase (saquinavir) soft gel capsule (FTV) in combination with low dose ritonavir [abstract I-330]. Program and abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1999 Sep 26–29; San Francisco. Washington, DC: American Society for Microbiology, 1999Google Scholar
  13. 13.
    Wood R, Trepo C, Livrozet J, et al. Enhancement of pharmacokinetic parameters of amprenavir when combined with low dose ritonavir (APV 600 mg/RTV 100mg BID) and preliminary efficacy results [abstract 283]. AIDS 2000; 14 Suppl. 4: S98Google Scholar
  14. 14.
    Hugen P, Burger DM, ter Hofstede HJM, et al. Dose-finding study of a once-daily indinavir/ritonavir regimen. J Acquir Immune Defic Syndr 2000; 25(3): 236–45PubMedCrossRefGoogle Scholar
  15. 15.
    Saah AJ, Winchell G, Seniuk M, et al. Multiple dose pharmacokinetics (PK) and tolerability of indinavir (IDV) ritonavir combinations in healthy volunteers [abstract 362]. Program and abstracts of the 6th Conference on Retroviruses and Opportunistic Infections; 1999 Jan 31–Feb 4; Chicago. Alexandria (VA): Foundation for Retrovirology and Human Health, 1999Google Scholar
  16. 16.
    Hsu A, Chiu YO, Hutman W, et al. Pharmacokinetic interactions between ritonavir and amprenavir [abstract 546]. Program and abstracts of the 12th International AIDS Conference. Durban; 2000 Jul 9–14; South Africa. Fairfield (MN): Marathon Multimedia, 2000Google Scholar
  17. 17.
    Molla A, Granneman GR, Sun E, et al. Recent developments in HIV protease inhibitor therapy. Antiviral Res 1998; 39: 1–23PubMedCrossRefGoogle Scholar
  18. 18.
    Boden D, Markowitz M. Resistance to human immunodeficiency virus type 1 protease inhibitors. Antimicrob Agents Chemother 1998; 42: 2775–83PubMedGoogle Scholar
  19. 19.
    Amprenavir (Agenerase®) [package insert]. Research Triangle Park (NC): Glaxo Wellcome, 1999Google Scholar
  20. 20.
    Garraffo R, Demarles D, Durant J, et al. Amprenavir (APV) plasma and intracellular concentrations when coadministered with ritonavir (RTV) in twice and once daily regimen in HIV-infected patients [abstract A-489]. Program and abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy; 2001 Sep 22–25; Chicago. Washington, DC: American Society for Microbiology, 2001Google Scholar
  21. 21.
    Atazanavir (Reyataz®) [package insert]. Princeton (NJ): BMS Virology, 2003Google Scholar
  22. 22.
    O’Mara E, Mummaneni V, Bifano M, et al. Pilot study of the interaction between BMS-232632 and ritonavir [abstract 740]. Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections; 2001 Feb 4–8; Chicago. Alexandria (VA): Foundation for Retrovirology and Human Health, 2001Google Scholar
  23. 23.
    Indinavir (Crixivan®) [package insert]. West Point (PA): Merck, 2000Google Scholar
  24. 24.
    van Heeswijk RPG, Veldkamp AI, Hoetelmans RMW, et al. The steady-state plasma pharmacokinetics of indinavir alone and in combination with a low dose of ritonavir in twice daily dosing regimens in HIV-1 infected individuals. AIDS 1999; 13(14): F95–9PubMedCrossRefGoogle Scholar
  25. 25.
    Gerber JG, Acosta EP, Wu H, et al. Pharmacokinetic (PK) comparison of two indinavir (IDV)/ritonavir (RTV) regimens in salvage therapy [abstract TuPeB4552]. Programs and abstracts of the 14th International AIDS Conference; 2002 Jul 7–12; Barcelona. Fairfield (MN): Marathon Multimedia, 2002Google Scholar
  26. 26.
    Squires K, Riddler S, Havlir D, et al. Co-administration of indinavir (IDV) 1200mg and nelfinavir (NFV) 1250mg in a twice-daily regimen: preliminary safety, pharmacokinetic (PK), and antiviral activity [abstract 364]. Program and abstracts of the 6th Conference on Retroviruses and Opportunistic Infections; 1999 Jan 31–Feb 4; Chicago. Alexandria (VA): Foundation for Retrovirology and Human Health, 1999Google Scholar
  27. 27.
    Murphy RL, Brun S, Hicks C, et al. ABT-378/ritonavir plus stavudine and lamivudine for the treatment of antiretroviralnaive adults with HIV-1 infection: 48-week results. AIDS 2001; 15(1): F1–9PubMedCrossRefGoogle Scholar
  28. 28.
    Nelfinavir (Viracept®) [package insert]. La Jolla (CA): Agouron, 2000Google Scholar
  29. 29.
    Kurowski M, Kaeser B, Sawyer A, et al. Low-dose ritonavir moderately enhances nelfinavir exposure. Clin Pharmacol Ther 2002; 72(2): 123–32PubMedCrossRefGoogle Scholar
  30. 30.
    Khaliq Y, Gallicano K, Sahai J, et al. Effect of nelfinavir on short and long-term plasma exposure of saquinavir in hard gel capsule during tid and bid dosing regimens [abstract P43]. Program and abstracts of the 4th International Congress on Drug Therapy in HIV Infection; 1998 Nov 8–12; Glasgow, UKGoogle Scholar
  31. 31.
    Danner SA, Carr A, Leonard JM, et al. A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease. N Engl J Med 1995; 33: 1528–33CrossRefGoogle Scholar
  32. 32.
    Saquinavir (Fortovase®) [package insert]. Nutley (NJ): Roche, 2000Google Scholar
  33. 33.
    Cameron DW, Japour AJ, Xu Y, et al. Ritonavir and saquinavir combination therapy for the treatment of HIV infection. AIDS 1999; 13(2): 213–24PubMedCrossRefGoogle Scholar
  34. 34.
    Veldkamp AI, van Heeswijk RPG, Mulder JW, et al. Steady-state pharmacokinetics of twice-daily dosing of saquinavir plus ritonavir in HIV-1-infected individuals. J Acquir Immune Defic Syndr 2001; 27(4): 344–9PubMedGoogle Scholar
  35. 35.
    Buss N, Snell P, Bock J, et al. Saquinavir and ritonavir pharmacokinetics following combined ritonavir and saquinavir (soft gelatin capsules) administration. Br J Clin Pharamcol 2001; 52: 255–64CrossRefGoogle Scholar
  36. 36.
    Hsu A, Granneman GR, Cao G, et al. Pharmacokinetic interactions between two human immunodeficiency virus protease inhibitors, ritonavir and saquinavir. Clin Pharmacol Ther 1998; 63: 453–64PubMedCrossRefGoogle Scholar
  37. 37.
    Gisolf EH, van Heeswijk RPG, Hoetelmans RWM, et al. Decreased exposure to saquinavir in HIV-1 infected patients after long-term antiretroviral therapy including ritonavir and saquinavir. AIDS 2000; 14: 801–5PubMedCrossRefGoogle Scholar
  38. 38.
    Merry C, Barry MG, Mulcahy F, et al. Saquinavir pharmacokinetics alone and in combination with ritonavir in HIV-infected patients. AIDS 1997; 11(4): F29–33PubMedCrossRefGoogle Scholar
  39. 39.
    Michelet C, Bellisant E, Delfraissy JF, et al. Safety and efficacy of a combination of ritonavir and saquinavir added to AZT + 3TC in HIV infected patients: pilot study ANRS 069 [abstract 1-202]. Program and abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto. Washington (DC): Americal Society for Microbiology, 1997Google Scholar
  40. 40.
    Condra JH, Schleif WA, Blahy OM, et al. In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature 1995; 374: 569–71PubMedCrossRefGoogle Scholar
  41. 41.
    Puig T, Bonjoch A, Ruiz L, et al. Usefulness of ritonavir and saquinavir combination therapy for HIV-advanced patients failing on indinavir [abstract I-201]. Program and abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto. Washington, DC: American Society for Microbiology. 1997Google Scholar
  42. 42.
    Deeks SG, Grant RM, Beatty GW, et al. Activity of a ritonavir plus saquinavir-containing regimen in patients with virologic evidence of indinavir or ritonavir failure. AIDS 1998; 12(10): F97–102PubMedCrossRefGoogle Scholar
  43. 43.
    Rhone SA, Hogg RS, Yip B, et al. The antiviral effect of ritonavir and saquinavir in combination amongst HIV-infected adults: results from a community-based study. AIDS 1998; 12(6): 619–24PubMedCrossRefGoogle Scholar
  44. 44.
    Lallemand F, Adda N, Schneider V, et al. Prospective follow-up of 67 indinavir-experienced HIV/AIDS patients treated with ritonavir/saquinavir combination [abstract I-194]. Programs and abstracts of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1998 Sep 24–27; San Diego. Washington DC: American Society for Microbiology, 1998Google Scholar
  45. 45.
    Hall CS, Raines CP, Barnett SH, et al. Efficacy of salvage therapy containing ritonavir and saquinavir after failure of single protease inhibitor containing regimens. AIDS 1999; 13(10): 1207–12PubMedCrossRefGoogle Scholar
  46. 46.
    Tebas P, Patick AK, Kane EM, et al. Virologic responses to ritonavir-saquinavir-containing regimen in patients who had previously failed nelfinavir. AIDS 1999; 13(2): F23–8PubMedCrossRefGoogle Scholar
  47. 47.
    Cahn P, Dragsted UB, Pedersen C, et al. Week 48 data of a randomized trial to evaluated safety and efficacy of indinavir/ritonavir (800/100mg bid) versus saquinavir/ritonavir (1000/100mg bid) in adult HIV-1 infection [abstract WeOrB1265]. Programs and abstracts of the 14th International AIDS Conference; 2002 Jul 7–12; Barcelona. Fairfield (MN): Marathon Multimedia, 2002Google Scholar
  48. 48.
    Youle M, Gerstoft J, Fox Z, et al. The final week 48 analysis of phase IV, randomized, open-label, multi-centre trial to evaluate safety and efficacy of lopinavir/ritonavir (400/100mg bid) versus saquinavir/ritonavir (1000/100mg bid) in adult HIV-1 infection: the MaxCmin2 trial [abstract LB23]. Program and abstracts of the 2nd IAS Conference on HIV Pathogenesis and Treatment; 2003 July 13–16; ParisGoogle Scholar
  49. 49.
    Lin JH, Chen I-W, Vastag KJ, et al. pH-dependent oral absorption of L-735,524, a potent HIV protease inhibitor, in rats and dogs. Drug Metab Dispos 1995; 23: 730–5PubMedGoogle Scholar
  50. 50.
    Yeh KC, Deutsch P, Haddix H, et al. Single-dose pharmacokinetics of indinavir and the effect of food. Antimicrob Agents Chemother 1998; 42: 332–8PubMedGoogle Scholar
  51. 51.
    Hsu A, Granneman GR, Cao G, et al. Indinavir can be taken with regular meals when administered with ritonavir [abstract 22361]. Programs and abstracts of the 12th World AIDS Conference; 1998 June 28–Jul 3; Geneva. Fairfield (MN): Marathon Multimedia, 1998Google Scholar
  52. 52.
    Saah AJ, Winchell AG, Nessly ML, et al. Pharmacokinetic profile and tolerability of indinavir-ritonavir combinations in healthy volunteers. Antimicrob Agents Chemother 2001; 45(10): 2710–5PubMedCrossRefGoogle Scholar
  53. 53.
    Ghosn J, Lamotte C, Ait-Mohand H, et al. Efficacy of a twice-daily antiretroviral regimen containing 100mg ritonavir/400mg indinavir in HIV-infected patients. AIDS 2003; 17: 209–14PubMedCrossRefGoogle Scholar
  54. 54.
    Burger DM, Hugen PWH, Aarnoutse RE, et al. A retrospective, cohort-based survey of patients using twice-daily indinavir + ritonavir combinations: pharmacokinetics, safety, and efficacy. J Acquir Immune Defic Syndr 2001 Mar 1; 26(3): 218–24PubMedCrossRefGoogle Scholar
  55. 55.
    Boyd M, Duncombe C, Ruxrungtham K, et al. Indinavir TID vs. Indinavir/ritonavir BID in combination with AZT/3TC for HIV infection in nucleoside pretreated patients: HIV-NAT 005 76-week follow-up [abstract 422-w]. Programs and abstracts of the 9th Conference on Retroviruses and Opportunistic Infections; 2002 Feb 24–28; Seattle. Alexandria (VA): Foundation for Retrovirology and Human Health, 2002Google Scholar
  56. 56.
    Young B, Baker R, Gallant J, et al. Effectiveness and safety of ritonavir (RTV)/indinavir (IDV) containing antiretroviral therapy: a retrospective multi-center clinical cohort study [abstract 1522]. Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2000 Sep 17–20; Toronto. Washington, DC: American Society for Microbiology, 2000Google Scholar
  57. 57.
    Sadler BM, Gillotin C, Lou Y, et al. Pharmacokinetic study of human immunodeficiency virus protease inhibitors used in combination with amprenavir. Antimicrob Agents Chemother 2001; 45(12): 3663–8PubMedCrossRefGoogle Scholar
  58. 58.
    Sadler BM, Piliero PJ, Preston SL, et al. Pharmacokinetic (PK) drug-interaction between amprenavir (APV) and ritonavir (RTV) in HIV-seronegative subjects after multiple, oral dosing [abstract 77]. Program and abstracts of the 7th Conference on Retroviruses and Opportunistic Infections; 2000 Jan 30–Feb 2; San Francisco. Alexandria (VA): Foundation for Retrovirology and Human Health, 2000Google Scholar
  59. 59.
    Sale M, Sadler BM, Stein DS. Pharmacokinetic modeling and simulations of interaction of amprenavir and ritonavir. Antimicrob Agents Chemother 2002; 46(3): 746–54PubMedCrossRefGoogle Scholar
  60. 60.
    Wood R, Wire MB, Lancaster CT, et al. An assessment of plasma amprenavir (APV) pharmacokinetics (PK) following long-term administration of Agenerase (AGN) and low-dose ritonavir (RTV) QD in HIV-infected adult subjects (APV20001 and COL30500) [abstract 2.6]. Program and abstracts of the 3rd International Workshop on Clinical Pharmacology of HIV Therapy; 2002 Apr 11–13; Washington, DC. Utrecht, NL: Virology Education BV, 2002Google Scholar
  61. 61.
    Piscitelli S, Bechtel C, Sadler B, et al. The addition of a second protease inhibitor eliminates amprenavir-efavirenz drug interactions and increases plasma amprenavir concentrations [abstract 78]. Program and abstracts of the 7th Conference on Retroviruses and Opportunistic Infections; 2000 Jan 30–Feb 2; San Francisco. Alexandria (VA): Foundation for Retrovirology and Human Health, 2000Google Scholar
  62. 62.
    Duval X, Le Moing V, Longuet P, et al. Efavirenz-induced decrease in plasma amprenavir levels in human immunodeficiency virus-infected patients and correction by ritonavir [letter]. Antimicrob Agents Chemother 2000; 44(9): 2593PubMedCrossRefGoogle Scholar
  63. 63.
    Degen O, Kurowski M, van Lunzen J, et al. Steady-state plasma pharmacokinetics of amprenavir (APV) 450mg bid and ritonavir (RTV) 200mg bid with or without efavirenz (EFV) in HIV-1 infected individuals [abstract WeOrB547]. Program and abstracts of the 13th International Conference on AIDS; 2000 Jul 9–14; Durban. Fairfield (MN): Marathon Multimedia, 2000Google Scholar
  64. 64.
    Forsamprenavir (Lexiva®) [package insert]. Research Triangle Park (NC): Glaxo Smith Klein, 2003Google Scholar
  65. 65.
    De Jesus E, La Marca A, Sension M, et al. The context study: efficacy and safety of GW433908/RTV in PI-experienced subjects with virologic failure (24 week results) [abstract 178]. Program and abstracts of the 10th Conference on Retroviruses and Opportunistic Infections; 2003 Feb 10–14; Boston, Alexandria (VA): Foundation for Retrovirology and Human Health, 2003Google Scholar
  66. 66.
    Wood R, Trepo C, Livrozet JM, et al. Amprenavir (APV) 600 mg/ritonavir (RTV) 100mg BID or APV 1200mg/RTV 200mg QD given in combination with abacavir (ABC) and lamivudine (3TC) maintains efficacy in ART-naive HIV-1-infected adults over 12 weeks (APV20001) [abstract 332]. Programs and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections; 2001 Feb 4–8; Chicago. Alexandria (VA): Foundation for Retrovirology and Human Health, 2001Google Scholar
  67. 67.
    Markowitz M, Hurley A, Ramratnam B, et al. The safety and efficacy of a ritonavir-boosted amprenavir-based regiment after switch from amprenavir-based HAART [abstract 405]. Programs and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections; 2001 Feb 4–8; Chicago. Alexandria (VA): Foundation for Retrovirology and Human Health, 2001Google Scholar
  68. 68.
    Katlama C, Schneider L, Agher R, et al. Ritonavir (RTV)/amprenavir (APV) combination therapy in HIV infected patients who failed several protease inhibitor containing regimen [abstract 673]. Programs and abstracts of the 1st International AIDS Society Conference on HIV Pathogenesis and Treatment; 2001 Jul 8–11; Buenos AiresGoogle Scholar
  69. 69.
    Sham HL, Kempf DJ, Molla A, et al. ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrob Agents Chemother 1998; 42: 3218–24PubMedGoogle Scholar
  70. 70.
    Lal R, Hsu A, Chen P, et al. Single dose pharmacokinetics of ABT-378 in combination with ritonavir [abstract 1-194]. Programs and abstracts of the 37th Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto. Washington, DC: American Society for Microbiology, 1997Google Scholar
  71. 71.
    Lal R, Hsu A, Granneman GR, et al. Multiple dose safety, tolerability and pharmacokinetics of ABT-378 in combination with ritonavir [abstract 647]. Program and abstracts of the 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5; Chicago. Alexandria (VA): Foundation for Retrovirology and Human Health, 1998Google Scholar
  72. 72.
    Bertz R, Foit C, Ye X, et al. Pharmacokinetics of once-daily vs. twice daily Kaletra (lopinavir/ritonavir) in HIV+ subjects [abstract 126]. Program and abstracts of the 9th Conference on Retroviruses and Opportunistic Infections; 2002 Feb 24–28; Seattle. Alexandria (VA): Foundation for Retrovirology and Human Health, 2002Google Scholar
  73. 73.
    Benson C, King M, Brun S, et al. ABT-378/ritonavir (ABT-378/r) in antiretroviral-naîve HIV+ patients: 96 weeks [abstract 546]. Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2000 Sep 17–20; Toronto. Washington, DC: American Society for Microbiology, 2000Google Scholar
  74. 74.
    Walmsley S, Badley A, Beall G, et al. Efficacy of ABT-378/r vs. nelfinavir (NFV) in antiretroviral (ARV)-naîve subjects: results of a phase III blinded randomized clinical trial [abstract 693]. Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2000 Sep 17–20; Toronto. Washington, DC: American Society for Microbiology, 2000Google Scholar
  75. 75.
    Johnson M, Beall G, Badley A, et al. ABT-378/ritonavir (ABT-378/r) versus nelfinavir in antiretroviral naîve subjects: week 48 comparison in a phase III blinded randomized clinical trial [abstract PL6.5]. Program and abstracts of the 5th International Congress on Drug Therapy in HIV Infection; 2000 Oct 22–26; GlasgowGoogle Scholar
  76. 76.
    Feinberg J, Brun S, Xu Y, et al. Durable suppression of HIV+ RNA after 2 years of therapy with ABT-378/ritonavir (ABT-378/r) treatment in single protease inhibitor experienced patients [abstract P101]. Program and abstracts of the 5th International Congress on Drug Therapy in HIV Infection; 2000 Oct 22–26; GlasgowGoogle Scholar
  77. 77.
    De Mendoza C, Martin-Carbonero L, Gallego O, et al. Response to lopinavir in multiple PI/NNRTI-experienced patients [abstract 670]. Program and abstracts of the 1st International AIDS Society Conference on HIV Pathogenesis and Treatment; 2001 Jul 8–11; Buenos AiresGoogle Scholar
  78. 78.
    Becker S. The pharmacology of atazanavir [online]. Available from URL: http://www.medscape.com/viewarticle/442247 [Accessed 2004 Jan 12]
  79. 79.
    Haas D, Zala C, Schrader S, et al. Once-daily atazanavir plus saquinavir favorably affects total cholesterol (TC) and fasting triglyceride (TG) profiles in patients failing prior PI therapy (trial AI424-009, wk 24) [abstract LB-16]. Program and abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy; 2001 Sep 22–25; Chicago. Washington, DC: American Society for Microbiology, 2001Google Scholar
  80. 80.
    Agarwala S, Russo R, Mummaneni V, et al. Steady-state pharmacokinetic (PK) interaction study of atazanvir (ATV) with ritonavir (RTV) in healthy subjects [abstract H-1716]. Progam and abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy; 202 Sep 27039; San Diego. Washington (DC): American Society for Microbiology, 2002Google Scholar
  81. 81.
    Taburet AM, Piketty C, Gerard L, et al. Pharmacokinetic (PK) parameters of atazanavir (ATV)/ritonavir (RTV) when combined to tenofovir (TDF) in HIV-infected patients with multiple treatment failures: a substudy of Puzzle2-ANRS 107 trial [abstract 537]. Program and abstracts of the 10th Conference on Retroviruses and Opportunistic Infections; 2002 Feb 10–14; Boston. Alexandria (VA): Foundation for Retrovirology and Human Health, 2002Google Scholar
  82. 82.
    Preston S, Piliero P, O’Mara E, et al. Evaluation of steady-state interaction between atazanavir (ATV) and efavirenz (EFV) [abstract 443-W]. Program and abstracts of the 9th Conference on Retroviruses and Opportunistic Infections; 2002 Feb 24–28; Seattle. Alexandria (VA): Foundation for Retrovirology and Human Health, 2002Google Scholar
  83. 83.
    O’Mara E, Agawala S, Randall D, et al. Steady-state pharmacokinetic interaction study of atazanavir (ATV) with efavirenz (EFV) and ritonavir (RTV) in healthy subjects [abstract 444-W]. Program and abstracts of the 9th Conference on Retroviruses and Opportunistic Infections; 2002 Feb 24–28; Seattle. Alexandria (VA): Foundation for Retrovirology and Human Health, 2002Google Scholar
  84. 84.
    Merry C, Barry MG, Mulcahy F, et al. Saquinavir pharmacokinetics alone and in combination with nelfinavir in HIV-infected patients. AIDS 2001; 11(15): F117–20CrossRefGoogle Scholar
  85. 85.
    Lalezari J, Siemon-Hryczyk P, Feinberg J, et al. Tidbid study 48 week analysis: Fortovase (FTV) TID regimen compared to RTV BID or FTV + NFV BID regimens in HIV-1 infected patients [abstract TUPeB3229]. Program and abstracts of the 13th International Conference on AIDS; 2000 Jul 9–14; Durban. Fairfield (MN): Marathon Multimedia, 2000Google Scholar
  86. 86.
    Havlir DV, Riddler S, Squires K, et al. Co-administration of indinavir and nelfinavir in a twice daily regimen: preliminary safety, pharmacokinetic and anti-viral activity results [abstract 393]. Program and abstracts of the 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5; Chicago. Alexandria (VA): Foundation for Retrovirology and Human Health, 1998Google Scholar
  87. 87.
    Gallant JE, Heath-Chiozzi M, Raines C, et al. Phase II study of nelfinavir-ritonavir combination therapy: an update. Program and abstracts of the 12th World AIDS Conference; 1998 Jun 28–Jul 3; Geneva. Fairfield (MN): Marathon Multimedia, 1998Google Scholar
  88. 88.
    Zhang PH, Pithavala YK, Lee CA, et al. Apparent genetic polymorphism in nelfinavir metabolism: evaluation of clinical relevance [abstract 264]. Proceedings of the Twelfth International Symposium on Microsomes and Drug Oxidations; 1998 Jul 20–24; Montpellier. Montpellier: The Symposium, 1998Google Scholar
  89. 89.
    Flexner C, Hsu A, Kerr B, et al. Steady-state pharmacokinetic interactions between ritonavir (RTV), nelfinavir (NFV), and the nelfinavir active metabolite M8 (AG1402) [abstract 42265]. Program and abstracts of the 12th World AIDS Conference; 1998 Jun 28–Jul 3, Geneva. Fairfield, MN: Marathon Multimedia, 1998Google Scholar
  90. 90.
    McCallister S, Sabo J, Galitz L, et al. An open-label steady state investigation of the pharmacokinetics (PK) of tipranavir (TPV) and ritonavir (RTV) and their effects on cytochrome P-450 (3A4) activity in normal healthy volunteers (BI 1182.5) [abstract 434-W]. Program and abstracts of the 7th Conference on Retroviruses and Opportunistic Infections; 2000 Jan 30–Feb 2; San Francisco. Alexandria (VA): Foundation for Retrovirology and Human Health, 2002Google Scholar
  91. 91.
    Wang Y, Daenzer C, Wood R, et al. The safety, efficacy and viral dynamics analysis of tipranavir, a new-generation protease inhibitor, in a phase II study in antiretroviral naîve HIV-I infected patients [abstract 673]. Program and abstracts of the 7th Conference on Retroviruses and Opportunistic Infections; 2000 Jan 30–Feb 2; San Francisco. Alexandria (VA): Foundation for Retrovirology and Human Health, 2002Google Scholar
  92. 92.
    Schwartz R, Kazanjian P, Slater L, et al. Resistance to tipranavir is uncommon in a randomized trial of tipranavir/ritonavir (TPV/RTV) in multiple PI-failure patients (BI 1182.2) [abstract 562-T]. Program and abstracts of the 9th Conference on Retroviruses and Opportunistic Infections. 2002 Feb 24–28; Seattle. Alexandria (VA): Foundation for Retrovirology and Human Health, 2002Google Scholar
  93. 93.
    Condra JH, Petropoulous CJ, Ziermann R, et al. Drug resistance and predicted virologic responses to human immunodeficiency virus type 1 protease inhibitor therapy. J Infect Dis 2000; 182(3): 758–65PubMedCrossRefGoogle Scholar
  94. 94.
    Baxter JD, Merigan TC, Wentworth DN, et al. Both baseline HIV-1 drug resistance and antiretroviral drug levels are associated with short-term virologic responses to salvage therapy. AIDS 2002; 16(8): 1131–8PubMedCrossRefGoogle Scholar
  95. 95.
    Schmidt B, Korn K, Moschik B, et al. Low level of cross-resistance to amprenavir (141W94) in samples from patients pretreated with other protease inhibitors. Antimicrob Agents Chemother 2000; 44(11): 3213–6PubMedCrossRefGoogle Scholar
  96. 96.
    Benson CA, Deeks SG, Brun SC, et al. Safety and antiviral activity at 48 weeks of lopinavir/ritonavir plus nevirapine and 2 nucleoside reverse-transcriptase inhibitors in human immunodeficiency virus type 1-infected protease inhibitor-experienced patients. J Infect Dis 2002; 185(5): 599–607PubMedCrossRefGoogle Scholar
  97. 97.
    Rockstroh J, Brun S, Bertz R, et al. Kaletra (ABT-378/ritonavir) and efavirenz: 48-week safety/efficacy evaluation in multiple PI-experienced patients [abstract F150]. Program and abstracts of the 5th International Congress on Drug Therapy in HIV Infection; 2000 Oct 22–26; GlasgowGoogle Scholar
  98. 98.
    Meynard JL, Poirier JM, Guiard-Schmid JB, et al. Impact of ABT 378/r on the amprenavir (APV) plasma concentrations in HIV-experienced patients treated by the association APV-ABT 378/r [abstract I-1736]. Program and abstracts of the 41st International Conference on Antimicrobial Agents and Chemotherapy; 2001 Sep 22–25; Chicago. Washington, DC: American Society for Microbiology, 2001Google Scholar
  99. 99.
    Peytavin G, Lamotte C, Duval X, et al. Amprenavir (APV) plasma concentrations are dramatically decreased by the association with ABT378/r in HIV-infected patients (Pts) [abstract 1.14]. Programs and abstracts of the 2nd International Workshop on Clinical Pharmacology of HIV Therapy; 2001 Apr 2–4; Noordwijk. Utrecht (NL): Virology Education BV, 2001Google Scholar
  100. 100.
    Baldini F, Rizzo MG, Hoetelmans RMW, et al. A prospective study of deep salvage therapy with lopinavir/r, amprenavir, and NRTIs: final 24-week data, pharmacokinetics, and association of drug levels/drug susceptibility with virologic response [abstract 423-w]. Program and abstracts of the 9th Conference on Retroviruses and Opportunistic Infections; 2002 Feb 24–28; Seattle. Alexandria (VA): Foundation for Retrovirology and Human Health, 2002Google Scholar
  101. 101.
    LeTiec C, Barrail A, Vincent I, et al. Pharmacokinetic parameters of amprenavir (APV), lopinavir (LPV) and ritonavir (RTV) when combined in HIV-infected patients with multiple treatment failures [abstract 7.13]. Program and abstracts of the 3rd International Workshop on Clinical Pharmacology of HIV Therapy. 2002 Apr 11–13; Washington, DC. Utrecht (NL): Virology Education BV, 2002Google Scholar
  102. 102.
    Raguin G, Taburet AM, Chene G, et al. Pharmacokinetic parameters and virological response to the combination of lopinavir/ritonavir (LPV/r) and amprenavir (APV) in HIV-infected patients with multiple treatment failures: week 6 results of Puzzle 1-ANRS study [abstract 420-w]. Program and abstracts of the 9th Conference on Retroviruses and Opportunistic Infections; 2002 Feb 24–28; Seattle. Alexandria (VA): Foundation for Retrovirology and Human Health, 2002Google Scholar
  103. 103.
    Solas C, Quinson AM, Couprie C, et al. Pharmacokinetic interaction between lopinavir/r and amprenavir in salvage therapy [abstract 440-w]. Program and abstracts of the 9th Conference on Retroviruses and Opportunistic Infections; 2002 Feb 24–28; Seattle. Alexandria (VA): Foundation for Retrovirology and Human Health, 2002Google Scholar
  104. 104.
    Zilly M, Langmann P, Vaeth T, et al. Effects of efavirenz and/or lopinavir/r on amprenavir plasma levels in HAART [abstract 7.8]. Program and abstracts of the 3rd International Workshop on Clinical Pharmacology of HIV Therapy; 2002 Apr 11–13; Washington, DC. Utrecht (NL): Virology Education BV, 2002Google Scholar
  105. 105.
    Bertz R, Foit C, Burt D, et al. Assessment of the multiple dose pharmacokinetic interaction between Kaletra (lopinavir/ritonavir) and amprenavir in healthy volunteers [abstract 7.6]. Program and abstracts of the 3rd International Workshop on Clinical Pharmacology of HIV Therapy; 2002 Apr 11–13; Washington, DC. Utrecht (NL): Virology Education BV, 2002Google Scholar
  106. 106.
    Vanig TJ, Brill M. Decreased plasma concentrations of amprenavir and lopinavir in patients on this combination [abstract MoPpB2009]. Program and abstracts of the 14th International AIDS Conference; 2002 Jul 7–12; Barcelona. Fairfield (MN): Marathon Multimedia, 2002Google Scholar
  107. 107.
    Khanlou H, Graham E, Brill M, et al. Drug interaction between amprenavir and lopinavir/ritonavir in salvage therapy. AIDS 2002; 16(5): 797–8PubMedCrossRefGoogle Scholar
  108. 108.
    Stein A, Brothers CH, Scott TR. Effect of reduced-dose amprenavir in combination with lopinavir on plasma levels of amprenavir in patients infected with HIV. Clin Ther 2001; 23(3): 513–5PubMedCrossRefGoogle Scholar
  109. 109.
    DeJesus E, Oritz R, Bellos N, et al. An investigation to determine amprenavir and lopinavir/ritonavir plasma trough concentrations when co-administered. Program and abstracts of the 3rd International Workshop on Clinical Pharmacology of HIV Therapy; 2002 Apr 11–13; Washington, DC. Utrecht (NL): Virology Education BV, 2002Google Scholar
  110. 110.
    Gatti G, De Pascalis CR, DeLuca A, et al. Pharmacokinetics and virologic outcome with amprenavir/ritonavir or amprenavir/lopinavir/ritonavir. Program and abstracts of the 3rd International Workshop on Clinical Pharmacology of HIV Therapy; 2002 Apr 11–13 Washington, DC. Utrecht (NL): Virology Education BV, 2002Google Scholar
  111. 111.
    Mauss S, Schmutz G, Kuschak D, et al. Unfavourable interaction of amprenavir and lopinavir in combination with ritonavir?. AIDS 2002; 16: 296–7PubMedCrossRefGoogle Scholar
  112. 112.
    Loutfy M, Thompson C, Trpeski M, et al. Clinical efficacy of salvage regimens containing both amprenavir and lopinavir/ritonavir as compared to salvage regimens containing only lopinavir/ritonavir stratified by NNRTI-experience [abstract TuPeB4558]. Program and abstracts of the 14th International AIDS Conference; 2002 Jul 7–12; Barcelona. Fairfield (MN): Marathon Multimedia, 2002Google Scholar
  113. 113.
    Zala C, Patterson P, Coll P, et al. Virological response and safety at 48 weeks of double boosted protease inhibitors with lopinavir/r plus either saquinavir or amprenavir in heavily pretreated HIV infected persons [abstract TuPeB4492]. Program and abstracts of the 14th International AIDS Conference; 2002 Jul 7–12; Barcelona. Fairfield (MN): Marathon Multimedia, 2002Google Scholar
  114. 114.
    Kashuba ADM, Tierney C, Downy GF, et al. Combining GW443908 (fosamprenavir; 908) with lopinavir/ritonavir (LPV/R) in HIV-1 infected adults results in substantial reductions in amprenavir (APV) and LPV concentrations: pharmacokinetic (PK) results from adult ACTG Protocol A5143 [abstract H-855a]. Program and abstracts of the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy Agents; 2003 Sep14–17; Chicago. Washington (DC): American Society for Microbiology, 2003Google Scholar
  115. 115.
    Molla A, Mo H, Vasavanonda S, et al. In vitro antiviral interaction of lopinavir with other protease inhibitors. Antimicrob Agents Chemother 2002; 46(7): 2249–53PubMedCrossRefGoogle Scholar
  116. 116.
    Smith GHR, Klien M, Murphy T, et al. Double boosted salvage therapy with lopinavir (LOP)/ritonavir (RIT) and saquinavirsgc (SQR) in HIV-1 infected patients having failed 3 antiretroviral classes [abstract TuPeB4547]. Program and abstracts of the 14th International AIDS Conference; 2002 Jul 7–12; Barcelona. Fairfield (MN): Marathon Multimedia, 2002Google Scholar
  117. 117.
    Hellinger J, Morris A, Piscitelli S, et al. Pilot study of saquinavir-SGC (Fortovase, SQV) 1000mg twice daily and lopinavir/ritonavir (Kaletra, LPV/r) in protease inhibitor-experienced HIV+ individuals: dose escalation and combined normalized inhibitory quotient (cNIQ) [abstract 451-W]. Program and abstracts of the 9th Conference on Retroviruses and Opportunistic Infections; 2002 Feb 24–28; Seattle. Alexandria (VA): Foundation for Retrovirology and Human Health, 2002Google Scholar
  118. 118.
    la Porte C, Wasmuth JC, Burger DM, et al. Lopinavir/ritonavir plus saquinavir in salvage therapy; pharmacokinetics, tolerability and efficacy [abstract 7.14]. Program and abstracts of the 3rd International Workshop on Clinical Pharmacology of HIV Therapy; 2002 Apr 11–13; Washington, DC. Utrecht (NL): Virology Education BV, 2002Google Scholar
  119. 119.
    Staszewski S, Dauer B, Stephan C, et al. Pharmacokinetic profile monitoring as an augmentation to therapy evaluation in patients taking a simple boosted double protease-inhibitor regimen of lopinavir/r plus saquinavir without reverse transcriptase inhibitors [abstract 2.4]. Program and abstracts of the 3rd International Workshop on Clinical Pharmacology of HIV Therapy; 2002 Apr 11–13; Washington, DC. Utrecht (NL): Virology Education BV, 2002Google Scholar
  120. 120.
    Wolfe PR, Anderson P, Gunawan S. Simultaneous administration of amprenavir and saquinavir does not appear to lower plasma levels of either agent when coadministered with low-dose ritonavir [abstract 7.11]. Program and abstracts of the 3rd International Workshop on Clinical Pharmacology of HIV Therapy; 2002 Apr 11–13; Washington, DC. Utrecht (NL): Virology Education BV, 2002Google Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  • Jennifer R. King
    • 1
  • Heather Wynn
    • 2
  • Richard Brundage
    • 3
  • Edward P. Acosta
    • 1
  1. 1.Division of Clinical Pharmacology, School of MedicineUniversity of Alabama at BirminghamBirminghamUSA
  2. 2.Department of Laboratory Medicine and Pathology, School of MedicineUniversity of MinnesotaMinneapolisUSA
  3. 3.Department of Experimental and Clinical Pharmacology, School of PharmacyUniversity of MinnesotaMinneapolisUSA

Personalised recommendations