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01.11.2004 | Review Article

Practical Guidelines to Interpret Plasma Concentrations of Antiretroviral Drugs

verfasst von: Dr Bregt S. Kappelhoff, Kristel M. L. Crommentuyn, Monique M. R. de Maat, Jan W. Mulder, Alwin D. R. Huitema, Jos H. Beijnen

Erschienen in: Clinical Pharmacokinetics | Ausgabe 13/2004

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Abstract

Several relationships have been reported between antiretroviral drug concentrations and the efficacy of treatment, and toxicity. Therefore, therapeutic drug monitoring (TDM) may be a valuable tool in improving the treatment of HIV-1-infected patients in daily practice.

In this regard, several measures of exposure have been studied, e.g. trough and maximum concentrations, concentration ratios and the inhibitory quotient. However, it has not been unambiguously established which pharmacokinetic parameter should be monitored to maintain optimal viral suppression. Each pharmacokinetic parameter has its pros and cons. Many factors can affect the pharmacokinetics of antiretroviral agents, resulting in variability in plasma concentrations between and within patients. Therefore, plasma concentrations should be considered on several occasions. In addition, the interpretation of the drug concentration of a patient should be performed on an individual basis, taking into account the clinical condition of the patient. Important factors herewith are viral load, immunology, occurrence of adverse events, resistance pattern and comedication.

In spite of the described constraints, the aim of this review is to provide a practical guide for TDM of antiretroviral agents. This article outlines pharmacokinetic target values for the HIV protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir, and the non-nucleoside reverse transcriptase inhibitors efavirenz and nevirapine. Detailed advice is provided on how to interpret the results of TDM of these drugs.

Moyle GJ, Back D. Principles and practice of HIV-protease inhibitor pharmacoenhancement. HIV Med 2001; 2: 105–13PubMedCrossRef

Aarnoutse RE, Schapiro JM, Boucher CAB, et al. Therapeutic drug monitoring: an aid to optimising response to antiretroviral drugs. Drugs 2003; 63: 741–53PubMedCrossRef

Acosta EP, Gerber JG, and the Adult Pharmacology Committee of the AIDS Clinical Trials Group. Position paper on therapeutic drug monitoring of antiretroviral agents. AIDS Res Hum Retroviruses 2002; 18: 825–34PubMedCrossRef

Back DJ, Blaschke TF, Boucher CAB, et al. Optimising TDM in HIV clinical care: a practical guide to performing therapeutic drug monitoring (TDM) for antiretroviral agents [online]. Available from URL: http://www.hivpharmacology.com [Accessed 2004 Jul 27]

Fauci As, JG Bartlett. Guidelines for the use of antiretroviral agents in UIV-infected adults and adolescents [online]. Available from URL: http://www.aidsinfo.nih.gov [Accessed 2004 Jul 27]

Fletcher CV. Clinical significance of antiretroviral drug levels. HIV/AIDS: annual update 2001 [online]. Available from URL: http://www.medscape.com [Accessed 2004 Jul 27]

Marzolini C, Telenti A, Decosterd LA, et al. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS 2001; 15: 71–5PubMedCrossRef

Joshi AS, Barrett JS, Fiske WD, et al. Population pharmacokinetics of efavirenz in phase II studies and relationship with efficacy [abstract 1201]. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1999 Sep 26–29; San Francisco

Solas C, Basso S, Poizot-Martin I, et al. High indinavir Cmin is associated with higher toxicity in patients on indinavirritonavir 800/100mg twice-daily regimen. J Acquir Immune Defic Syndr 2002; 29: 374–7PubMed

10.

Langmann P, Zilly M, Weissbrich B, et al. Therapeutic drug monitoring of indinavir in HIV-infected patients undergoing HAART. Infection 2002; 30: 13–6PubMedCrossRef

11.

Lamotte C, Descamps D, Joly V, et al. Validation of an algorithm for indinavir (IDV) dosage adjustment (IADA) in patients with high IDV trough plasma concentration (Cmin) to prevent adverse events (AE) in an easy and potent IDV/ritonavir (RTV) containing regimen [abstract 4.3]. 3rd International Workshop on Clinical Pharmacology of HIV Therapy; 2002 Apr 11–13; Washington, DC

12.

Dumon C, Solas C, Thuret I, et al. Relationship between efficacy, tolerance, and plasma drug concentration of ritonavir in children with advanced HIV infection. Ther Drug Monit 2000; 22: 402–8PubMedCrossRef

13.

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

14.

Veldkamp AI, Weverling GJ, Lange JMA, et al. High exposure to nevirapine in plasma is associated with an improved virological response in HIV-1-infected individuals. AIDS 2001; 15: 1089–95PubMedCrossRef

15.

Côrte-Real R, Pereira S, Branco T, et al. Routine quantification of efavirenz plasma concentrations in HIV-1-infected individuals during two years [abstract 6.14]. 5th International Workshop on Clinical Pharmacology of HIV Therapy; 2004 Apr 1–3; Rome

16.

Bonora S, Gonzales de Requena D, Garazzino S, et al. Impact of nevirapine (NVP) trough concentrations (Ctrough) on time to achieve and time of maintenance of viral suppression (VS) in HIV+ patients taking NVP-based regimens [abstract 6.10]. 5th International Workshop on Clinical Pharmacology of HIV Therapy; 2004 Apr 1–3; Rome

17.

de Vries-Sluijs TE, Dieleman JP, Arts D, et al. Low nevirapine plasma concentrations predict virological failure in an unselected HIV-1-infected population. Clin Pharmacokinet 2003; 42(6): 599–605PubMedCrossRef

18.

Hoetelmans RMW, Van Heeswijk RPG, Meenhorst PL. Plasma concentrations of saquinavir determine HIV-1 RNA response over a 48-week period [abstract 42261]. 12th World Aids Conference; 1998 Jun 28–Jul 3; Geneva

19.

Burger DM, Hugen PWH, Aarnoutse RE, et al. Treatment failure of nelfinavir-containing triple therapy can largely be explained by low nelfinavir plasma concentrations. Ther Drug Monit 2003; 25(1): 73–80PubMedCrossRef

20.

Kempf D, Hsu A, Isaacson J, et al. Evaluation of the inhibitory quotient as a pharmacodynamic predictor of the virologic response to protease inhibitor therapy [abstract 7.3]. 2nd International Workshop on Clinical Pharmacology; 2001 Apr 2–4; Noordwijk

21.

Hugen PWH, Burger DM, Aarnoutse RE, et al. Therapeutic drug monitoring of HIV-protease inhibitors to assess noncompliance. Ther Drug Monit 2002; 24: 579–87PubMedCrossRef

22.

Núñez M, González de Requena D, Gallego L, et al. Higher efavirenz plasma levels correlate with development of insomnia. J Acquir Immune Defic Syndr 2001; 28: 399–400PubMed

23.

Dieleman JP, Gyssens IC, Van der Ende ME, et al. Urological complaints in relation to indinavir plasma concentrations in HIV-infected patients. AIDS 1999; 13: 473–8PubMedCrossRef

24.

Gatti G, Di Biagio A, Casazza R, et al. The relationship between ritonavir plasma levels and side-effects: implications for therapeutic drug monitoring. AIDS 1999; 13: 2083–9PubMedCrossRef

25.

Montaner J, Hill A, Acosta E. Practical implications for the interpretation of minimum plasma concentration/inhibitory concentration ratios. Lancet 2001; 357: 1438–40PubMedCrossRef

26.

Rousseau A, Marquet P. Application of pharmacokinetic modelling to the routine therapeutic drug monitoring of anticancer drugs. Fundam Clin Pharmacol 2002; 16(4): 253–62PubMedCrossRef

27.

De Maat MMR, Ekhart GC, Huitema ADR, et al. Drug interactions between antiretroviral drugs and comedicated agents. Clin Pharmacokinet 2003; 42: 223–82PubMedCrossRef

28.

Yeni PG, Hammer SM, Carpenter CCJ, et al. Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS Society-USA Panel. JAMA 2002; 288: 222–35PubMedCrossRef

29.

Breilh D, Pellegrin I, Rouzes A, et al. Virological, intracellular and plasma pharmacological parameters predicting response to lopinavir/ritonavir (KALEPHAR study). AIDS 2004; 18(9): 1305–10PubMedCrossRef

30.

Boffito M, Arnaudo I, Raiteri R, et al. Clinical use of lopinavir/ritonavir in a salvage therapy setting: pharmacokinetics and pharmacodynamics. AIDS 2002; 16: 2081–3PubMedCrossRef

31.

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

32.

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; 333: 1528–33PubMedCrossRef

33.

Valer L, De Mendoza C, González de Requena D, et al. Impact of HIV genotyping and drug levels on the response to salvage therapy with saquinavir/ritonavir. AIDS 2002; 16: 1964–6PubMedCrossRef

34.

Peyriere H, Mauboussin JM, Rouanet I, et al. Management of sudden psychiatric disorders related to efavirenz. AIDS 2001; 15: 1323–4PubMedCrossRef

35.

Gonzalez De Requena D, Núñez M, Gallego O, et al. Does an increase in nevirapine plasma levels cause complete virologic suppression in patients experiencing early virological failure? HIV Clin Trials 2002; 6: 463–7

36.

González de Requena D, Núñez M, Jiménez-Nácher I, et al. Liver toxicity caused by nevirapine. AIDS 2002; 16: 290–1PubMedCrossRef

37.

de Maat MMR, ter Heine R, Mulder JW, et al. Incidence and risk factors for nevirapine-associated rash. Eur J Clin Pharmacol 2003; 59(5–6): 457–62PubMedCrossRef

38.

de Maat MMR, Mathôt RA, Veldkamp AI, et al. Hepatotoxicity following nevirapine-containing regimens in HIV-1-infected individuals. Pharmacol Res 2002; 46(3): 295–300PubMedCrossRef

39.

Sarasa M, Miró J, Knobel H, et al. Nevirapine plasma concentrations at two weeks neither predicts nevirapine-associated rash nor liver toxicity [abstract 6.5]. 5th International Workshop on Clinical Pharmacology of HIV Therapy; 2004 Apr 1–3; Rome

40.

European Agency for the Evaluation of Medicinal Products. EMEA public statement on Viramune (nevirapine): severe and life-threatening cutaneous and hepatic reactions [online]. Available from http://www.emea.eu.int/pdfs/human/press/pus/1126000EN.pdf [Accessed 2004 Sep 6]

41.

Gonzalez de Requena D, Marrone R, Canta F, et al. Influence of atazanavir pharmacokinetics on both early virological response and bilirubin elevations [abstract 6.15]. 5th International Workshop on Clinical Pharmacology of HIV Therapy; 2004 Apr 1–3; Rome

42.

O’Mara E, Cirincione B, Mummaneni V, et al. Population pharmacodynamic (PD) assessment of the safety and antiretroviral activity of BMS-232632 [abstract A-507]. 41st Interscience Conference on Antimicrobial Agents and Chemotherapy; 2001 Dec 16–19; Chicago

43.

Taburet AM, Piketty C, Chazallon C, et al. Interactions between atazanavir-ritonavir and tenofovir in heavily pretreated human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 2004; 48(6): 2091–6PubMedCrossRef

44.

Preston S, Piliero P, O’Mara E, et al. Evaluation of steady-state interaction between atazanavir (ATV) and efavirenz (EFV) [abstract 443-W]. 9th Conference on Retroviruses and Opportunistic Infections; 2002 Feb 24–28; Seattle

45.

Taburet AM, Piketty C, Gérard L, et al. Pharmacokinetic parameters of atazanavir/ritonavir when combined to tenofovir in HIV infected patients with multiple treatment failures: a sub-study of Puzzle2-ANRS 107 trial [abstract 537]. 10th Conference on Retroviruses and Opportunistic Infections; 2003 Feb 10–14; Boston

46.

O’Mara E, Agarwala 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]. 9th Conference on Retroviruses and Opportunistic Infections; 2002 Feb 24–28; Seattle

47.

European Medicines Agency: Reyataz: European Public Assessment Report (EPAR) [online]. Available from URL: http://www.emea.eu.int/humandocs/Humans/EPAR/reyataz/reyataz.htm [Accessed 2004 Sep 9]

48.

Acosta EP, Henry K, Baken L, et al. Indinavir concentrations and antiviral effect. Pharmacotherapy 1999; 19: 708–12PubMedCrossRef

49.

Murphy RL, Sommadossi JP, Lamson M, et al. Antiviral effect and pharmacokinetic interaction between nevirapine and indinavir in persons infected with human immunodeficiency virus type I. J Infect Dis 1999; 179: 1116–23PubMedCrossRef

50.

Burger DM, Hoetelmans RMW, Hugen PWH, et al. Low plasma concentrations of indinavir are related to virological treatment failure in HIV-1-infected patients on indinavir-containing triple therapy. Antivir Ther 1998; 3: 215–20PubMed

51.

Anderson PL, Brundage RC, Kakuda TN, et al. CD4 response is correlated with peak plasma concentrations of indinavir in adults with undetectable human immunodeficiency virus ribonucleic acid. Clin Pharmacol Ther 2002; 71(4): 280–5PubMedCrossRef

52.

Van Heeswijk RPG, Veldkamp AI, Hoetelmans RMW, et al. The steady-state 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: F95–9PubMedCrossRef

53.

Saah AJ, Winchell G, Seniuk M, et al. Multiple-dose pharmacokinetics (PK) and tolerability of indinavir (IDV) ritonavir (RTV) combinations in healthy volunteers [abstract 362]. 6th Conference on Retroviruses and Opportunistic Infections; 1999 Jan 31–Feb 4; Chicago

54.

Eron JJ, Feinberg J, Kessler HA, et al. Once-daily versus twicedaily lopinavir/ritonavir in antiretroviral-naive HIV-positive patients: a 48-week randomised clinical trial. J Infect Dis 2004; 189(2): 265–72PubMedCrossRef

55.

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): 350–9PubMedCrossRef

56.

Burger DM, Hugen PWH, Reiss P, et al. Therapeutic drug monitoring of nelfinavir and indinavir in treatment-naive HIV-1-infected individuals. AIDS 2003; 17: 1157–65PubMedCrossRef

57.

Burger DM, Bergshoef A, de Groot R, et al. Maintaining the nelfinavir trough concentration above 0.8 mg/L significantly improves virological response in HIV-1-infected children [abstract 3.3]. 5th International Workshop on Clinical Pharmacology of HIV Therapy; 2004 Apr 1–3; Rome

58.

Baede-van Dijk PA, Hugen PWH, Verweij-van Wissen CPWGM, et al. Analysis of variation in plasma concentrations of nelfinavir and its active metabolite M8 in HIV-positive patients. AIDS 2001; 15: 991–8PubMedCrossRef

59.

Kurowski M, Kaeser B, Sawyer A, et al. Low-dose ritonavir moderately enhances nelfinavir exposure. Clin Pharmacol Ther 2002; 72: 123–32PubMedCrossRef

60.

Lorenzi P, Yerly S, Abderrakim K, et al. Toxicity, efficacy, plasma drug concentrations and protease mutations in patients with advanced HIV infection treated with ritonavir plus saquinavir. AIDS 1997; 11: F95–9PubMedCrossRef

61.

Hoetelmans RMW, Reijers MHE, Weverling GJ, et al. The effect of plasma drug concentrations on HIV-1 clearance rate during quadruple drug therapy. AIDS 1998; 12: F111–5PubMedCrossRef

62.

Schapiro JM, Winters MA, Stewart F, et al. The effect of highdose saquinavir on viral load and CD4+ T-cell counts in HIV-infected patients. Ann Intern Med 1996; 124: 1039–50PubMed

63.

Langmann P, Zilly M, Weissbrich B, et al. Therapeutic drug monitoring of saquinavir in patients during protease inhibitor therapy with saquinavir alone or in combination with ritonavir or nelfinavir. Eur J Med Res 2000; 5: 59–62PubMed

64.

Noble S, Faulds D. Saquinavir: a review of its pharmacology and clinical potential in the management of HIV infection. Drugs 1996; 52: 93–112PubMedCrossRef

Titel: Practical Guidelines to Interpret Plasma Concentrations of Antiretroviral Drugs
verfasst von: Dr Bregt S. Kappelhoff
Kristel M. L. Crommentuyn
Monique M. R. de Maat
Jan W. Mulder
Alwin D. R. Huitema
Jos H. Beijnen
Publikationsdatum: 01.11.2004
Verlag: Springer International Publishing
Erschienen in: Clinical Pharmacokinetics / Ausgabe 13/2004
Print ISSN: 0312-5963
Elektronische ISSN: 1179-1926
DOI: https://doi.org/10.2165/00003088-200443130-00002

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

Practical Guidelines to Interpret Plasma Concentrations of Antiretroviral Drugs

Abstract

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

Abstract

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