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Application and Impact of Population Pharmacokinetics in the Assessment of Antiretroviral Pharmacotherapy

Clinical Pharmacokinetics volume 44, pages 591–625 (2005)Cite this article

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Abstract

Population pharmacokinetics has been an important technique used to explore and define relevant sources of variation in drug exposure and response in patient populations. This has been especially true in the area of antiretroviral therapy where the assurance of adequate and sustained drug exposure of multiple agents is highly correlated with therapeutic success. Population pharmacokinetic analyses across the four drug classes and 20 US FDA-approved products used to treat HIV have been published to date. The published reports were predominantly based on actual clinical trials conducted in HIV-infected patients with one or more agents administered.

Modelling and simulation approaches have been used in the evaluation of antiretroviral agent outcomes incorporating problematic design and analysis factors such as sparse plasma sampling, data imbalance and censored data. Additional benefits of population modelling approaches applied to the investigation of antiretroviral agents include the ability to assess dosing compliance, understanding and quantifying drug-drug interactions in order to select dosing regimens and the screening of new drug candidates. Pharmacokinetic/pharmacodynamic models have been used to characterise the relationship between drug exposure and virological and immunological response, and to predict clinical outcome. These models offer the best opportunity for individualising and optimising patient therapy, particularly when adjusted for adherence/compliance.

The impact of population pharmacokinetics in the area of antiretroviral therapy can be directly assessed by its role in the validation of surrogate markers such as viral RNA load, therapeutic drug monitoring and the management of individual patient outcomes via exposure-toxicity relationships. Each of these population pharmacokinetic outcomes has contributed to the current regulatory environment, specifically in the area of accelerated approval of new antiretroviral agents.

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Notes

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

References

  1. Pomerantz RJ, Horn DL. Twenty years of therapy for HIV-1 infection. Nat Med 2003; 9(7): 867–73

    Article  PubMed  CAS  Google Scholar 

  2. Pfister M, Labbe L, Lu JF, et al. Effect of coadministration of nelfinavir, indinavir, and saquinavir on the pharmacokinetics of amprenavir. Clin Pharmacol Ther 2002; 72(2): 133–41

    Article  PubMed  CAS  Google Scholar 

  3. Decker CJ, Laitinen LM, Bridson GW, et al. Metabolism of amprenavir in liver microsomes: role of CYP3A4 inhibition for drug interactions. J Pharm Sci 1998; 87(7): 803–7

    Article  PubMed  CAS  Google Scholar 

  4. Korber BT, Allen EE, Farmer AD, et al. Heterogeneity of HIV-1 and HIV-2. AIDS 1995; 9 Suppl. A: S5–18

    PubMed  Google Scholar 

  5. Pfister M, Labbe L, Hammer SM, et al. Population pharmacokinetics and pharmacodynamics of efavirenz, nelfinavir and indinavir: Adult AIDS Clinical Trial Group Study 398. Antimicrob Agents Chemother 2003; 47(1): 130–7

    Article  PubMed  CAS  Google Scholar 

  6. Barry M, Mulcahy F, Merry C, et al. Pharmacokinetics and potential interactions amongst antiretroviral agents used to treat patients with HIV infection. Clin Pharmacokinet 1999; 36(4): 289–304

    Article  PubMed  CAS  Google Scholar 

  7. Physicians’ desk reference, 58th ed. Montvale (NJ): Thomson Healthcare, Inc., 2004

  8. Lu JF, Blaschke TF, Flexner C, et al. Model-based analysis of the pharmacokinetic interactions between ritonavir, nelfinavir, and saquinavir after simultaneous and staggered oral administration. Drug Metab Dispos 2002; 30(12): 1455–61

    Article  PubMed  CAS  Google Scholar 

  9. Pellegrin I, Breilh D, Montestruc F, et al. Virologic response to nelfinavir-based regimens: pharmacokinetics and drug resistance mutations (VIRAPHAR study). AIDS 2002; 16(10): 1331–40

    Article  PubMed  CAS  Google Scholar 

  10. Jackson KA, Rosenbaum SE, Kerr BM, et al. A population pharmacokinetic analysis of nelfinavir mesylate in human immunodeficiency virus-infected patients enrolled in a phase III clinical trial. Antimicrob Agents Chemother 2000; 44(7): 1832–7

    Article  PubMed  CAS  Google Scholar 

  11. Hsu A, Granneman FR, Japour A. Evaluation of potential ritonavir and indinavir combination BID regimens [abstract]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto

    Google Scholar 

  12. Vanhove GF, Gries JM, Verotta D, et al. Exposure-response relationships for saquinavir, zidovudine, and zalcitabine in combination therapy. Antimicrob Agents Chemother 1997; 41(11): 2433–8

    PubMed  CAS  Google Scholar 

  13. Vanhove GF, Kastrissios H, Gries JM, et al. Pharmacokinetics of saquinavir, zidovudine, and zalcitabine in combination therapy. Antimicrob Agents Chemother 1997; 41(11): 2428–32

    PubMed  CAS  Google Scholar 

  14. Lunn DJ, Aarons L. The pharmacokinetics of saquinavir: a Markov chain Monte Carlo population analysis. J Pharmacokinet Biopharm 1998; 26(1): 47–74

    PubMed  CAS  Google Scholar 

  15. Drusano GL, D’argenio DZ, Preston SL, et al. Use of drug effect interaction modeling with Monte Carlo simulation to examine the impact of dosing interval on the projected antiviral activity of the combination of abacavir and amprenavir. Antimicrob Agents Chemother 2000; 44(6): 1655–9

    Article  PubMed  CAS  Google Scholar 

  16. 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(8): 2052–60

    Article  PubMed  CAS  Google Scholar 

  17. Drusano GL, Yuen GJ, Morse G, et al. Impact of bioavailability on determination of the maximal tolerated dose of 2′,3′-dideoxyinosine in phase I trials. Antimicrob Agents Chemother 1992; 36(6): 1280–3

    Article  PubMed  CAS  Google Scholar 

  18. Adams JM, Shelton MJ, Hewitt RG, et al. Relationship between didanosine exposure and surrogate marker response in human immunodeficiency virus-infected outpatients. Antimicrob Agents Chemother 1998; 42(4): 821–6

    PubMed  CAS  Google Scholar 

  19. Harb GE, Mandema JW, Delahunty T, et al. Population pharmacokinetics of didanosine in patients with human immunodeficiency virus infection [letter]. J Infect Dis 1996; 173(1): 273

    Article  PubMed  CAS  Google Scholar 

  20. Pai SM, Shukla UA, Grasela TH, et al. Population pharmacokinetic analysis of didanosine (2′,3′-dideoxyinosine) plasma concentrations obtained in phase I clinical trials in patients with AIDS or AIDS-related complex. J Clin Pharmacol 1992; 32(3): 242–7

    PubMed  CAS  Google Scholar 

  21. Piscitelli SC, Amatea MA, Vogel S, et al. Effects of cytokines on antiviral pharmacokinetics: an alternative approach to assessment of drug interactions using bioequivalence guidelines. Antimicrob Agents Chemother 1996; 40(1): 161–5

    PubMed  CAS  Google Scholar 

  22. Zhou XJ, Sheiner LB, D’aquila RT, et al. Population pharmacokinetics of nevirapine, zidovudine, and didanosine in human immunodeficiency virus-infected patients. The National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group Protocol 241 Investigators. Antimicrob Agents Chemother 1999; 43(1): 121–8

    PubMed  CAS  Google Scholar 

  23. Pereira AS, Smeaton LM, Gerber JG, et al. The pharmacokinetics of amprenavir, zidovudine, and lamivudine in the genital tracts of men infected with human immunodeficiency virus type 1 (AIDS Clinical Trials Group Study 850). J Infect Dis 2002; 186(2): 198–204

    Article  PubMed  CAS  Google Scholar 

  24. Moore KH, Yuen GJ, Hussey EK, et al. Population pharmacokinetics of lamivudine in adult human immunodeficiency virus-infected patients enrolled in two phase III clinical trials. Antimicrob Agents Chemother 1999; 43(12): 3025–9

    PubMed  CAS  Google Scholar 

  25. Zhang L, Price R, Aweeka F, et al. Making the most of sparse clinical data by using a predictive-model-based analysis, illustrated with a stavudine pharmacokinetic study. Eur J Pharm Sci 2001; 12(4): 377–85

    Article  PubMed  CAS  Google Scholar 

  26. Horton CM, Dudley MN, Kaul S, et al. Population pharmacokinetics of stavudine (d4T) in patients with AIDS or advanced AIDS-related complex. Antimicrob Agents Chemother 1995; 39(10): 2309–15

    Article  PubMed  CAS  Google Scholar 

  27. Gries JM, Troconiz IF, Verotta D, et al. A pooled analysis of CD4 response to zidovudine and zalcitabine treatment in patients with AIDS and AIDS-related complex. Clin Pharmacol Ther 1997; 61(1): 70–82

    Article  PubMed  CAS  Google Scholar 

  28. Adams JM, Shelton MJ, Hewitt RG, et al. Zalcitabine population pharmacokinetics: application of radioimmunoassay. Antimicrob Agents Chemother 1998; 42(2): 409–13

    PubMed  CAS  Google Scholar 

  29. Collart L, Blaschke TF, Boucher F, et al. Potential of population pharmacokinetics to reduce the frequency of blood sampling required for estimating kinetic parameters in neonates. Dev Pharmacol Ther 1992; 18(1–2): 71–80

    PubMed  CAS  Google Scholar 

  30. Mirochnick M, Capparelli E, Dankner W, et al. Zidovudine pharmacokinetics in premature infants exposed to human immunodeficiency virus. Antimicrob Agents Chemother 1998; 42(4): 808–12

    PubMed  CAS  Google Scholar 

  31. Capparelli EV, Mirochnick M, Dankner WM, et al. Pharmacokinetics and tolerance of zidovudine in preterm infants. J Pediatr 2003; 142(1): 47–52

    Article  PubMed  CAS  Google Scholar 

  32. Capparelli EV, Englund JA, Connor JD, et al. Population pharmacokinetics and pharmacodynamics of zidovudine in HIV-infected infants and children. J Clin Pharmacol 2003; 43(2): 133–40

    Article  PubMed  CAS  Google Scholar 

  33. Sasomsin P, Mentre F, Diquet B, et al. Relationship between exposure to zidovudine and decrease of P24 antigenemia in HIV-infected patients in monotherapy. Fundam Clin Pharmacol 2002; 16(5): 347–52

    Article  PubMed  CAS  Google Scholar 

  34. Guidance for industry: exposure-response relationships. Study design, data analysis, and regulatory applications: draft guidance. Washington, DC: US Department of Health and Human Services, 2002 Mar

    Google Scholar 

  35. Gitterman SR, Drusano GL, Egorin MJ, et al. Population pharmacokinetics of zidovudine. The Veterans Administration Cooperative Studies Group. Clin Pharmacol Ther 1990; 48(2): 161–7

    Article  PubMed  CAS  Google Scholar 

  36. Mentre F, Escolano S, Diquet B, et al. Clinical pharmacokinetics of zidovudine: inter and intraindividual variability and relationship to long term efficacy and toxicity. Eur J Clin Pharmacol 1993; 45(5): 397–407

    Article  PubMed  CAS  Google Scholar 

  37. Polis MA, Piscitelli SC, Vogel S, et al. Clarithromycin lowers plasma zidovudine levels in persons with human immunodeficiency virus infection. Antimicrob Agents Chemother 1997; 41(8): 1709–14

    PubMed  CAS  Google Scholar 

  38. Barrett JS, Joshi AS, Chai M, et al. Population pharmacokinetic meta-analysis with efavirenz. Int J Clin Pharmacol Ther 2002; 40(11): 507–19

    PubMed  CAS  Google Scholar 

  39. Csajka C, Marzolini C, Fattinger K, et al. Population pharmacokinetics and effects of efavirenz in patients with human immunodeficiency virus infection. Clin Pharmacol Ther 2003; 73(1): 20–30

    Article  PubMed  CAS  Google Scholar 

  40. Villani P, Regazzi MB, Castelli F, et al. Pharmacokinetics of efavirenz (EFV) alone and in combination therapy with nelfinavir (NFV) in HIV-1 infected patients. Br J Clin Pharmacol 1999; 48(5): 712–5

    Article  PubMed  CAS  Google Scholar 

  41. De Maat MM, Huitema AD, Mulder JW, et al. Population pharmacokinetics of nevirapine in an unselected cohort of HIV-1-infected individuals. Br J Clin Pharmacol 2002; 54(4): 378–85

    Article  PubMed  Google Scholar 

  42. Soy D, Aweeka FT, Church JA, et al. Population pharmacokinetics of enfuvirtide in pediatric patients with human immunodeficiency virus: searching for exposure-response relationships. Clin Pharmacol Ther 2003; 74(6): 569–80

    Article  PubMed  CAS  Google Scholar 

  43. Koudriakova T, Iatsimirskaia 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): 552–61

    PubMed  CAS  Google Scholar 

  44. Lown KS, Ghosh M, Watkins PB. Sequences of intestinal and hepatic cytochrome P450 3A4 cDNAs are identical. Drug Metab Dispos 1998; 26(2): 185–7

    PubMed  CAS  Google Scholar 

  45. 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): 190–4

    Article  PubMed  CAS  Google Scholar 

  46. 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): 609–16

    PubMed  CAS  Google Scholar 

  47. Merry C, Barry MG, Mulcahy F, et al. Saquinavir pharmacokinetics alone and in combination with ritonavir in HIV-infected patients. AIDS 1997; 11(4): F29–33

    Article  PubMed  CAS  Google Scholar 

  48. Yuen G, Anderson R, Daniels R. Investigations of nelfinavir mesylate (NFV) pharmacokinetics (PK) interactions with indinavir (IDV) and ritonavir (RTV) [abstract]. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 28–Feb 2; Washington, DC

    Google Scholar 

  49. Kumar GN, Dykstra J, Roberts EM, et al. Potent inhibition of the cytochrome P-450 3A-mediated human liver microsomal metabolism of a novel HIV protease inhibitor by ritonavir: a positive drug-drug interaction. Drug Metab Dispos 1999; 27(8): 902–8

    PubMed  CAS  Google Scholar 

  50. Srinivas RV, Middlemas D, Flynn P, et al. Human immunodeficiency virus protease inhibitors serve as substrates for multidrug transporter proteins MDR1 and MRP1 but retain antiviral efficacy in cell lines expressing these transporters. Antimicrob Agents Chemother 1998; 42(12): 3157–62

    PubMed  CAS  Google Scholar 

  51. Huisman MT, Smit JW, Schinkel AH. Significance of P-glycoprotein for the pharmacology and clinical use of HIV protease inhibitors. AIDS 2000; 14(3): 237–42

    Article  PubMed  CAS  Google Scholar 

  52. Profit L, Eagling VA, Back DJ. Modulation of P-glycoprotein function in human lymphocytes and Caco-2 cell monolayers by HIV-1 protease inhibitors. AIDS 1999; 13(13): 1623–7

    Article  PubMed  CAS  Google Scholar 

  53. Hoetelmans RM, Reijers MH, Weverling GJ, et al. The effect of plasma drug concentrations on HIV-1 clearance rate during quadruple drug therapy. AIDS 1998; 12(11): F111–5

    Article  PubMed  CAS  Google Scholar 

  54. Dudley MN. Clinical pharmacokinetics of nucleoside antiretroviral agents. J Infect Dis 1995; 171 Suppl. 2: S99–112

    Article  PubMed  Google Scholar 

  55. Barbier O, Turgeon D, Girard C, et al. 3′-azido-3′-deoxythimidine (AZT) is glucuronidated by human UDP-glucuronosyl-transferase 2B7 (UGT2B7). Drug Metab Dispos 2000; 28(5): 497–502

    PubMed  CAS  Google Scholar 

  56. Veal GJ, Back DJ. Metabolism of zidovudine. Gen Pharmacol 1995; 26(7): 1469–75

    Article  PubMed  CAS  Google Scholar 

  57. Acosta EP, Page LM, Fletcher CV. Clinical pharmacokinetics of zidovudine: an update. Clin Pharmacokinet 1996; 30(4): 251–62

    Article  PubMed  CAS  Google Scholar 

  58. Piscitelli S, Vogel S, Sadler B. Effect of efavirenz (DMP266) in the pharmacokinetics of 141W94 in HIV infected patients [abstract]. 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 2–5; Chicago

    Google Scholar 

  59. Adkins JC, Noble S. Efavirenz. Drugs 1998; 56(6): 1055–64

    Article  PubMed  CAS  Google Scholar 

  60. Sustivaâ„¢ (efavirenz) capsules (product information). Princeton (NJ): Bristol-Myers Squibb Company, 2000

  61. Sahai J, Cameron W, Salgo M. Drug interaction study between saquinavir (SQV) and nevirapine (NVP) [abstract]. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 28–Feb 2; Washington, DC

    Google Scholar 

  62. Gagnier P, Myers M, Lamson M. Effect of nevirapine (NVP) on pharmacokinetics (PK) of indinavir (IDV) in HIV-1 patients [abstract]. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 28–Feb 2; Washington, DC

    Google Scholar 

  63. Lamson M, Gagnier P, Greguski R. Effect of nevirapine (NFP) on pharmacokinetics (PK) of ritonavir (RTV) in HIV-1 patients [abstract]. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 28–Feb 2; Washington, DC

    Google Scholar 

  64. Merry C, Barry MG, Mulcahy F, et al. The pharmacokinetics of combination therapy with nelfinavir plus nevirapine. AIDS 1998; 12(10): 1163–7

    Article  PubMed  CAS  Google Scholar 

  65. Murphy RL, Montaner J. Nevirapine: a review of its development, pharmacological profile and potential for clinical use. Expert Opin Invest Drugs 1996; 5: 1183–99

    Article  CAS  Google Scholar 

  66. Cox SR, Schneck DW, Herman BD. Delavirdine (DLV) and nefinavir (NFV): a pharmacokinetic (PK) drug-drug interaction study in healthy adult volunteers [abstract]. 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 2–5; Chicago

    Google Scholar 

  67. Cox SR, Ferry JJ, Batts DH. Delavirdine and marketed protease inhibitors: pharamcokinetic interaction studies in healthy volunteers [abstract]. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 28–Feb 2; Washington, DC

    Google Scholar 

  68. Ferry JJ, Herman BD, Cox SR. Delavirdine (DLV) and indinavir (IDV): a pharmacokinetic (PK) drug-drug interaction study in healthy adult volunteers [abstract]. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 28–Feb 2; Washington, DC

    Google Scholar 

  69. Morse GD, Shelton MJ, Hewitt RG. Ritonavir (RIT) pharmacokinetics (PK) during combination therapy with delavirdine [abstract]. 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 2–5; Chicago

    Google Scholar 

  70. Kilby JM, Hopkins S, Venetta TM, et al. Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nat Med 1998; 4(11): 1302–7

    Article  PubMed  CAS  Google Scholar 

  71. Baba M, Nishimura O, Kanzaki N, et al. A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proc Natl Acad Sci U S A 1999; 96(10): 5698–703

    Article  PubMed  CAS  Google Scholar 

  72. Fuzeon (enfuvirtide) prescribing information. Nutley (NJ): Roche Laboratories Inc, 2003

  73. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med 1997; 337(11): 725–33

    Article  PubMed  CAS  Google Scholar 

  74. Kulkosky J, Nunnari G, Otero M, et al. Intensification and stimulation therapy for human immunodeficiency virus type 1 reservoirs in infected persons receiving virally suppressive highly active antiretroviral therapy. J Infect Dis 2002; 186(10): 1403–11

    Article  PubMed  CAS  Google Scholar 

  75. Wit FW, Van Leeuwen R, Weverling GJ, et al. Outcome and predictors of failure of highly active antiretroviral therapy: one-year follow-up of a cohort of human immunodeficiency virus type 1-infected persons. J Infect Dis 1999; 179(4): 790–8

    Article  PubMed  CAS  Google Scholar 

  76. Ledergerber B, Egger M, Opravil M, et al. Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study. Swiss HIV Cohort Study. Lancet 1999; 353(9156): 863–8

    Article  PubMed  CAS  Google Scholar 

  77. Sheiner LB, Rosenberg B, Marathe VV. Estimation of population characteristics of pharmacokinetic parameters from routine clinical data. J Pharmacokinet Biopharm 1977; 5(5): 445–79

    PubMed  CAS  Google Scholar 

  78. Sheiner LB, Beal SL. Evaluation of methods for estimating population pharmacokinetics parameters: I. Michaelis-Menten model: routine clinical pharmacokinetic data. J Pharmacokinet Biopharm. 1980; 8(6): 553–71

    PubMed  CAS  Google Scholar 

  79. Hochhaus G, Barrett JS, Derendorf H. Evolution of pharmacokinetics and pharmacokinetic/dynamic correlations during the 20th century. J Clin Pharmacol 2000; 40(9): 908–17

    Article  PubMed  CAS  Google Scholar 

  80. Guidance for industry: population pharmacokinetics. Washington, DC: US Department of Health and Human Services, 1999

  81. Ellner PD, Neu HC. The inhibitory quotient: a method for interpreting minimum inhibitory concentration data. JAMA 1981; 246(14): 1575–8

    Article  PubMed  CAS  Google Scholar 

  82. Hsu A, Isaacson J, Brun S, et al. Pharmacokinetic-pharmacodynamic analysis of lopinavir-ritonavir in combination with efavirenz and two nucleoside reverse transcriptase inhibitors in extensively pretreated human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 2003; 47(1): 350–9

    Article  PubMed  CAS  Google Scholar 

  83. Sale M, Sadler BM, Stein DS. Pharmacokinetic modeling and simulations of interaction of amprenavir and ritonavir. Antimicrob Agents Chemother 2002; 46(3): 746–54

    Article  PubMed  CAS  Google Scholar 

  84. Letendre SL, Capparelli EV, Ellis RJ, et al. Indinavir population pharmacokinetics in plasma and cerebrospinal fluid. The HIV Neurobehavioral Research Center Group. Antimicrob Agents Chemother 2000; 44(8): 2173–5

    Article  PubMed  CAS  Google Scholar 

  85. Zhou XJ, Havlir DV, Richman DD, et al. Plasma population pharmacokinetics and penetration into cerebrospinal fluid of indinavir in combination with zidovudine and lamivudine in HIV-1-infected patients. AIDS 2000; 14(18): 2869–76

    Article  PubMed  CAS  Google Scholar 

  86. Martin C, Sonnerborg A, Svensson JO, et al. Indinavir-based treatment of HIV-1 infected patients: efficacy in the central nervous system. AIDS 1999; 13(10): 1227–32

    Article  PubMed  CAS  Google Scholar 

  87. Mirochnick M, Capparelli E, Connor J. Pharmacokinetics of zidovudine in infants: a population analysis across studies. Clin Pharmacol Ther 1999; 66(1): 16–24

    Article  PubMed  CAS  Google Scholar 

  88. Marimoutou C, Chene G, Mercie P, et al. Prognostic factors of combined viral load and CD4+ cell count responses under triple antiretroviral therapy, Aquitaine cohort, 1996–1998. J Acquir Immune Defic Syndr 2001; 27(2): 161–7

    PubMed  CAS  Google Scholar 

  89. Mellors JW, Munoz A, Giorgi JV, et al. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med 1997; 126(12): 946–54

    PubMed  CAS  Google Scholar 

  90. Thiebaut R, Chene G, Jacqmin-Gadda H, et al. Time-updated CD4+ T lymphocyte count and HIV RNA as major markers of disease progression in naive HIV-1-infected patients treated with a highly active antiretroviral therapy: the Aquitaine cohort, 1996–2001. J Acquir Immune Defic Syndr 2003; 33(3): 380–6

    Article  PubMed  CAS  Google Scholar 

  91. Ormaasen V, Bruun JN, Sandvik L, et al. Prognostic value of changes in CD4 count and HIV RNA during the first six months on highly active antiretroviral therapy in chronic human immunodeficiency virus infection. Scand J Infect Dis 2003; 35(6–7): 383–8

    Article  PubMed  Google Scholar 

  92. Giorgi JV, Lyles RH, Matud JL, et al. Predictive value of immunologic and virologic markers after long or short duration of HIV-1 infection. J Acquir Immune Defic Syndr 2002; 29(4): 346–55

    PubMed  Google Scholar 

  93. Malhotra U, Bosch RJ, Chan E, et al. Association of T cell proliferative responses and phenotype with virus control in chronic progressive HIV-1 disease. J Infect Dis 2004; 189(3): 515–9

    Article  PubMed  Google Scholar 

  94. Vray M, Meynard JL, Dalban C, et al. Predictors of the virological response to a change in the antiretroviral treatment regimen in HIV-1-infected patients enrolled in a randomized trial comparing genotyping, phenotyping and standard of care (Narval trial, ANRS 088). Antivir Ther 2003; 8(5): 427–34

    PubMed  CAS  Google Scholar 

  95. Falloon J, Ait-Khaled M, Thomas DA, et al. HIV-1 genotype and phenotype correlate with virological response to abacavir, amprenavir and efavirenz in treatment-experienced patients. AIDS 2002; 16(3): 387–96

    Article  PubMed  CAS  Google Scholar 

  96. Meynard JL, Vray M, Morand-Joubert L, et al. Phenotypic or genotypic resistance testing for choosing antiretroviral therapy after treatment failure: a randomized trial. AIDS 2002; 16(5): 727–36

    Article  PubMed  Google Scholar 

  97. 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(10): 1333–9

    Article  PubMed  CAS  Google Scholar 

  98. Kulkosky J, Sullivan J, Xu Y, et al. Genotypic alteration of HAART-persistent HIV-1 reservoirs in vivo. Virology 2003; 314(2): 617–29

    Article  PubMed  CAS  Google Scholar 

  99. Hu DJ, Dondero TJ, Rayfield MA, et al. The emerging genetic diversity of HIV: the importance of global surveillance for diagnostics, research, and prevention. JAMA 1996; 275(3): 210–6

    Article  PubMed  CAS  Google Scholar 

  100. Moore J, Anderson R. The WHO and why of HIV vaccine trials. Nature 1994; 372(6504): 313–4

    Article  PubMed  CAS  Google Scholar 

  101. Darby SC, Doll R, Thakrar B, et al. Time from infection with HIV to onset of AIDS in patients with haemophilia in the UK. Stat Med 1990; 9(6): 681–9

    Article  PubMed  CAS  Google Scholar 

  102. McDonald RA, Mayers DL, Chung RC, et al. Evolution of human immunodeficiency virus type 1 env sequence variation in patients with diverse rates of disease progression and T-cell function. J Virol 1997; 71(3): 1871–9

    PubMed  CAS  Google Scholar 

  103. Lukashov VV, Kuiken CL, Goudsmit J. Intrahost human immunodeficiency virus type 1 evolution is related to length of the immunocompetent period. J Virol 1995; 69(11): 6911–6

    PubMed  CAS  Google Scholar 

  104. Hsu A, Granneman GR, Witt G, et al. Multiple-dose pharmacokinetics of ritonavir in human immunodeficiency virus-infected subjects. Antimicrob Agents Chemother 1997; 41(5): 898–905

    PubMed  CAS  Google Scholar 

  105. Wade JR, Kelman AW, Howie CA, et al. Effect of misspecification of the absorption process on subsequent parameter estimation in population analysis. J Pharmacokinet Biopharm 1993; 21(2): 209–22

    PubMed  CAS  Google Scholar 

  106. FDA. Current modalities used in the treatment of HIV infection [online]. Available from URL: http://www.fda.gov/oashi/aids/status.html [Accessed 2005 Apr 22]

  107. Perry CM, Balfour JA. Didanosine: an update on its antiviral activity, pharmacokinetic properties and therapeutic efficacy in the management of HIV disease. Drugs 1996; 52(6): 928–62

    Article  PubMed  CAS  Google Scholar 

  108. Mandema JW, Verotta D, Sheiner LB. Building population pharmacokinetic: pharmacodynamic models: I. Models for covariate effects. J Pharmacokinet Biopharm 1992; 20(5): 511–28

    PubMed  CAS  Google Scholar 

  109. Drusano GL, Moore KH, Kleim JP, et al. Rational dose selection for a nonnucleoside reverse transcriptase inhibitor through use of population pharmacokinetic modeling and Monte Carlo simulation. Antimicrob Agents Chemother 2002; 46(3): 913–6

    Article  PubMed  CAS  Google Scholar 

  110. Jackson RC. A pharmacokinetic-pharmacodynamic model of chemotherapy of human immunodeficiency virus infection that relates development of drug resistance to treatment intensity. J Pharmacokinet Biopharm 1997; 25(6): 713–30

    PubMed  CAS  Google Scholar 

  111. Verotta D, Schaedeli F. Non-linear dynamics models characterizing long-term virological data from AIDS clinical trials. Math Biosci 2002; 176(2): 163–83

    Article  PubMed  Google Scholar 

  112. Drusano GL, Bilello JA, Preston SL, et al. Hollow-fiber unit evaluation of a new human immunodeficiency virus type 1 protease inhibitor, BMS-232632, for determination of the linked pharmacodynamic variable. J Infect Dis 2001; 183(7): 1126–9

    Article  PubMed  CAS  Google Scholar 

  113. Little RJA. Regression with missing X’s: a review. J Am Stat Assoc 1992; 87: 1227–37

    Google Scholar 

  114. Little RJA, Rubin DB. Statistical analysis with missing data. New York: John Wiley & Sons, 1986

    Google Scholar 

  115. Labbe L, Hammer SM, Mellors JW, et al. A Markov model for the effect of covariates including drug adherence on longitudinal viral response in HIV patients [abstract]. 105th American Society for Clinical Pharmacology and Therapeutics Meeting; 2004 Mar 24–27; Miami Beach

    Google Scholar 

  116. Hayes KG, Perl ML, Efron B. Application of the bootstrap statistical method to the tau-decay-mode problem. Phys Rev D Part Fields 1989; 39(1): 274–9

    Article  PubMed  CAS  Google Scholar 

  117. Egger M, Junghans C, Friis-Moller N, et al. Highly active antiretroviral therapy and coronary heart disease: the need for perspective. AIDS 2001; 15 Suppl. 5: S193–201

    Article  PubMed  CAS  Google Scholar 

  118. Lu J, Gries JM, Verotta D, et al. Selecting reliable pharmacokinetic data for explanatory analyses of clinical trials in the presence of possible noncompliance. J Pharmacokinet Pharmacodyn 2001; 28(4): 343–62

    Article  PubMed  CAS  Google Scholar 

  119. Girard P, Blaschke TF, Kastrissios H, et al. A Markov mixed effect regression model for drug compliance. Stat Med 1998; 17(20): 2313–33

    Article  PubMed  CAS  Google Scholar 

  120. Guidance for industry: general considerations for pediatric pharmacokinetic studies for drugs and biological products. Washington, DC: US Department of Health and Human Services, 1998

  121. King JR, Kimberlin DW, Aldrovandi GM, et al. Antiretroviral pharmacokinetics in the paediatric population: a review. Clin Pharmacokinet 2002; 41(14): 1115–33

    Article  PubMed  CAS  Google Scholar 

  122. Perelson AS, Essunger P, Cao Y, et al. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 1997; 387(6629): 188–91

    Article  PubMed  CAS  Google Scholar 

  123. Perelson AS, Neumann AU, Markowitz M, et al. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science 1996; 271(5255): 1582–6

    Article  PubMed  CAS  Google Scholar 

  124. Chun TW, Carruth L, Finzi D, et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 1997; 387(6629): 183–8

    Article  PubMed  CAS  Google Scholar 

  125. Moroni M, Antinori S. HIV and direct damage of organs: disease spectrum before and during the highly active antiretroviral therapy era. AIDS 2003; 17 Suppl. 1: S51–64

    Article  PubMed  Google Scholar 

  126. Pfister M, Zhang L, Hammarlund-Udenaes M, et al. Modeling of transfer kinetics at the serum-cerebrospinal fluid barrier in rabbits with experimental meningitis: application to grepafloxacin. Antimicrob Agents Chemother 2003; 47(1): 138–43

    Article  PubMed  CAS  Google Scholar 

  127. Nowak MA, May RM. Mathematical biology of HIV infections: antigenic variation and diversity threshold. Math Biosci 1991; 106(1): 1–21

    Article  PubMed  CAS  Google Scholar 

  128. Nowak MA, Bonhoeffer S, Shaw GM, et al. Anti-viral drug treatment: dynamics of resistance in free virus and infected cell populations. J Theor Biol 1997; 184(2): 203–17

    Article  PubMed  CAS  Google Scholar 

  129. Wein LM, D’amato RM, Perelson AS. Mathematical analysis of antiretroviral therapy aimed at HIV-1 eradication or maintenance of low viral loads. J Theor Biol 1998; 192(1): 81–98

    Article  PubMed  CAS  Google Scholar 

  130. Stafford MA, Corey L, Cao Y, et al. Modeling plasma virus concentration during primary HIV infection. J Theor Biol 2000; 203(3): 285–301

    Article  PubMed  CAS  Google Scholar 

  131. Wei X, Ghosh SK, Taylor ME, et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature 1995; 373(6510): 117–22

    Article  PubMed  CAS  Google Scholar 

  132. Wu H, Ding AA, De Gruttola V. Estimation of HIV dynamic parameters. Stat Med 1998; 17(21): 2463–85

    Article  PubMed  CAS  Google Scholar 

  133. Gieschke R, Fotteler B, Buss N, et al. Relationships between exposure to saquinavir monotherapy and antiviral response in HIV-positive patients. Clin Pharmacokinet 1999; 37(1): 75–86

    Article  PubMed  CAS  Google Scholar 

  134. Stein DS, Drusano GL. Modeling of the change in CD4 lymphocyte counts in patients before and after administration of the human immunodeficiency virus protease inhibitor indinavir. Antimicrob Agents Chemother 1997; 41(2): 449–53

    PubMed  CAS  Google Scholar 

  135. Stein DS, Fish DG, Bilello JA, et al. A 24-week open-label phase I/II evaluation of the HIV protease inhibitor MK-639 (indinavir). AIDS 1996; 10(5): 485–92

    Article  PubMed  CAS  Google Scholar 

  136. Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med 2002; 346(26): 2039–46

    Article  PubMed  CAS  Google Scholar 

  137. Huang Y, Rosenkranz SL, Wu H. Modeling HIV dynamics and antiviral response with consideration of time-varying drug exposures, adherence and phenotypic sensitivity. Math Biosci 2003; 184(2): 165–86

    Article  PubMed  CAS  Google Scholar 

  138. Lockwood PA, Cook JA, Ewy WE, et al. The use of clinical trial simulation to support dose selection: application to development of a new treatment for chronic neuropathic pain. Pharm Res 2003; 20(11): 1752–9

    Article  PubMed  CAS  Google Scholar 

  139. Kuti JL, Dandekar PK, Nightingale CH, et al. Use of Monte Carlo simulation to design an optimized pharmacodynamic dosing strategy for meropenem. J Clin Pharmacol 2003; 43(10): 1116–23

    Article  PubMed  CAS  Google Scholar 

  140. Gifford AL, Bormann JE, Shively MJ, et al. Predictors of self-reported adherence and plasma HIV concentrations in patients on multidrug antiretroviral regimens. J Acquir Immune Defic Syndr 2000; 23(5): 386–95

    PubMed  CAS  Google Scholar 

  141. Nieuwkerk PT, Sprangers MA, Burger DM, et al. Limited patient adherence to highly active antiretroviral therapy for HIV-1 infection in an observational cohort study. Arch Intern Med 2001; 161(16): 1962–8

    Article  PubMed  CAS  Google Scholar 

  142. Haubrich RH, Little SJ, Currier JS, et al. The value of patient-reported adherence to antiretroviral therapy in predicting virologic and immunologic response. California Collaborative Treatment Group. AIDS 1999; 13(9): 1099–107

    Article  PubMed  CAS  Google Scholar 

  143. Wainberg MA, Friedland G. Public health implications of antiretroviral therapy and HIV drug resistance. JAMA 1998; 279(24): 1977–83

    Article  PubMed  CAS  Google Scholar 

  144. Hirsch MS, Conway B, D’aquila RT, et al. Antiretroviral drug resistance testing in adults with HIV infection: implications for clinical management. International AIDS Society: USA Panel. JAMA 1998; 279(24): 1984–91

    Article  PubMed  CAS  Google Scholar 

  145. Vanhove GF, Schapiro JM, Winters MA, et al. Patient compliance and drug failure in protease inhibitor monotherapy. JAMA 1996; 276(24): 1955–6

    Article  PubMed  CAS  Google Scholar 

  146. Gallego O, De Mendoza C, Perez-Elias MJ, et al. Drug resistance in patients experiencing early virological failure under a triple combination including indinavir. AIDS 2001; 15(13): 1701–6

    Article  PubMed  CAS  Google Scholar 

  147. Bangsberg DR, Hecht FM, Charlebois ED, et al. Adherence to protease inhibitors, HIV-1 viral load, and development of drug resistance in an indigent population. AIDS 2000; 14(4): 357–66

    Article  PubMed  CAS  Google Scholar 

  148. Bangsberg DR, Charlebois ED, Grant RM, et al. High levels of adherence do not prevent accumulation of HIV drug resistance mutations. AIDS 2003; 17(13): 1925–32

    Article  PubMed  Google Scholar 

  149. Pekovic V, Mayanja H, Vjecha M, et al. Comparison of three composite compliance indices in a trial of self-administered preventive therapy for tuberculosis in HIV-infected Ugandan adults. Uganda-Case Western Reserve University Research Collaboration. J Clin Epidemiol 1998; 51(7): 597–607

    Article  PubMed  CAS  Google Scholar 

  150. Liu H, Golin CE, Miller LG, et al. A comparison study of multiple measures of adherence to HIV protease inhibitors. Ann Intern Med 2001; 134(10): 968–77

    PubMed  CAS  Google Scholar 

  151. Melbourne KM, Geletko SM, Brown SL, et al. Medication adherence in patients with HIV infection: a comparison of two measurement methods. AIDS Read 1999; 9(5): 329–38

    PubMed  CAS  Google Scholar 

  152. Vrijens B. Analyzing time-varying patterns of human exposure to xenobiotics and their biomedical impact. Ghent: University of Ghent, 2002

    Google Scholar 

  153. Girard P, Sheiner LB, Kastrissios H, et al. Do we need full compliance data for population pharmacokinetic analysis? J Pharmacokinet Biopharm 1996; 24(3): 265–82

    PubMed  CAS  Google Scholar 

  154. Hu C, Sale ME. A joint model for nonlinear longitudinal data with informative dropout. J Pharmacokinet Pharmacodyn 2003; 30(1): 83–103

    Article  PubMed  Google Scholar 

  155. Kastrissios H, Suarez JR, Katzenstein D, et al. Characterizing patterns of drug-taking behavior with a multiple drug regimen in an AIDS clinical trial. AIDS 1998; 12(17): 2295–303

    Article  PubMed  CAS  Google Scholar 

  156. Khoo SH, Gibbons SE, Back DJ. Therapeutic drug monitoring as a tool in treating HIV infection. AIDS 2001; 15 Suppl. 5: S171–81

    Article  PubMed  CAS  Google Scholar 

  157. Burger D, Hugen P, Droste J. Therapeutic drug monitoring (TDM) of nelfinavir (NFV) and indinavir (IDV) in treatment-näive patients improves therapeutic outcome after 1 year: results from ATHENA [abstract]. First IAS Conference on HIV Pathogenesis and Treatment; 2001 Jul 8–11, Buenos Aires

    Google Scholar 

  158. Gerber JG. Using pharmacokinetics to optimize antiretroviral drug-drug interactions in the treatment of human immunodeficiency virus infection. Clin Infect Dis 2000; 30 Suppl. 2: S123–9

    Article  PubMed  CAS  Google Scholar 

  159. Van Heeswijk RP, Veldkamp AI, Mulder JW, et al. The steady-state pharmacokinetics of nevirapine during once daily and twice daily dosing in HIV-1-infected individuals. AIDS 2000; 14(8): F77–82

    Article  PubMed  Google Scholar 

  160. Soldin OP, Elin RJ, Soldin SJ. Therapeutic drug monitoring in human immunodeficiency virus/acquired immunodeficiency syndrome: quo vadis? Arch Pathol Lab Med 2003; 127(1): 102–5

    PubMed  CAS  Google Scholar 

  161. Dasgupta A, Okhuysen PC. Pharmacokinetic and other drug interactions in patients with AIDS. Ther Drug Monit 2001; 23(6): 591–605

    Article  PubMed  CAS  Google Scholar 

  162. Van Heeswijk RP. Critical issues in therapeutic drug monitoring of antiretroviral drugs. Ther Drug Monit 2002; 24(3): 323–31

    Article  PubMed  Google Scholar 

  163. Trotta MP, Ammassari A, Cozzi-Lepri A, et al. Adherence to highly active antiretroviral therapy is better in patients receiving non-nucleoside reverse transcriptase inhibitor-containing regimens than in those receiving protease inhibitor-containing regimens. AIDS 2003; 17(7): 1099–102

    Article  PubMed  Google Scholar 

  164. Perno CF, Ceccherini-Silberstein F, De Luca A, et al. Virologic correlates of adherence to antiretroviral medications and therapeutic failure. J Acquir Immune Defic Syndr 2002; 31 Suppl. 3: S118–22

    Article  PubMed  Google Scholar 

  165. Boffito M, Back DJ, Hoggard PG, et al. Intra-individual variability in lopinavir plasma trough concentrations supports therapeutic drug monitoring. AIDS 2003; 17(7): 1107–8

    Article  PubMed  Google Scholar 

  166. Noormohamed SE, Henry WK, Rhame FS, et al. Strategies for control of zidovudine concentrations in serum. Antimicrob Agents Chemother 1995; 39(12): 2792–7

    Article  PubMed  CAS  Google Scholar 

  167. Food and Drug Administration. New drug, antibiotic, and biological drug product regulations; accelerated approval: final rule. Fed Regist 1992; 57: 58942–60

    Google Scholar 

  168. James JS. Editorial: time to end the death trials. AIDS Treat News 1996 Aug 2; (252): 1–4

    Google Scholar 

  169. Mitka M. Accelerated approval scrutinized: confirmatory phase 4 studies on new drugs languish. JAMA 2003; 289(24): 3227–9

    Article  PubMed  Google Scholar 

  170. Orlando VI. The FDA’s accelerated approval process: does the pharmaceutical industry have adequate incentives for self-regulation? Am J Law Med 1999; 25(4): 543–68

    PubMed  CAS  Google Scholar 

  171. Pau AK. Antiretroviral therapy-associated serious and life-threatening toxicities. Curr Infect Dis Rep 2003; 5(5): 429–38

    Article  PubMed  Google Scholar 

  172. Guidance for industry: pharmacokinetics in patients with impaired hepatic function: study design, data analysis, and impact on dosing and labeling. Washington, DC: US Department of Health and Human Services, 1999

  173. Guidance for industry: pharmacokinetics in patients with impaired renal function: study design, data analysis, and impact in dosing and labeling. Washington, DC: US Department of Health and Human Services, 1998

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Acknowledgements

We gratefully acknowledge Dr Lewis B. Sheiner and Dr Terrence Blaschke for their invaluable editorial and scientific evaluation of this manuscript. It is with a heavy heart that we dedicate this manuscript to our friend and mentor, Dr Lewis B. Sheiner, who passed away during the preparation of this manuscript. The authors have no conflicts of interest that are directly relevant to the content of this manuscript.

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Authors and Affiliations

  1. Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Jeffrey S. Barrett

  2. Faculty of Pharmacie, Université de Montreal, Montreal, Quebec, Canada

    Line Labbé

  3. Strategic Modeling and Simulation, Bristol-Myers Squibb, Princeton, New Jersey, USA

    Marc Pfister

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  1. Jeffrey S. Barrett
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  2. Line Labbé
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  3. Marc Pfister
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Correspondence to Jeffrey S. Barrett.

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Barrett, J.S., Labbé, L. & Pfister, M. Application and Impact of Population Pharmacokinetics in the Assessment of Antiretroviral Pharmacotherapy. Clin Pharmacokinet 44, 591–625 (2005). https://doi.org/10.2165/00003088-200544060-00003

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Keywords

  • Zidovudine
  • Ritonavir
  • Therapeutic Drug Monitoring
  • Efavirenz
  • Virological Response

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