nach oben

Clinical Pharmacokinetics

Erschienen in:

01.09.2007 | Review Article

Clinical Pharmacokinetics of Darunavir

verfasst von: Michael Rittweger, PD Dr. med. Keikawus Arastéh

Erschienen in: Clinical Pharmacokinetics | Ausgabe 9/2007

Einloggen, um Zugang zu erhalten

Abstract

Darunavir (TMC114) is a newly developed HIV-1 protease inhibitor with potent antiviral activity against both wild-type and multidrug resistant HIV-1 strains. The drug is currently approved by the US FDA for antiretroviral treatment-experienced patients with limited therapeutic options. The approved dosage of darunavir is 600mg in combination with ritonavir 100mg twice daily. Darunavir is rapidly absorbed after oral administration, reaching peak plasma concentrations after 2.5–4 hours. Absorption is followed by a fast distribution/elimination phase and a subsequent slower elimination phase with a terminal elimination half-life of 15 hours in the presence of low-dose ritonavir. Darunavir is approximately 95% plasma protein bound, mainly to α₁-acid glycoprotein. Systemic exposure is increased by 30% when darunavir is taken with a meal. Darunavir is extensively and almost exclusively metabolised by cytochrome P450 (CYP) 3A4. Coadministration with small doses of the strong CYP3A4 inhibitor ritonavir results in an increase in darunavir bioavailability from 37% to 82%. Darunavir and its metabolites are mainly excreted in faeces (79.5%) and, to a lesser extent, in urine (13.9%). With regard to the necessary coadministration with low-dose ritonavir as a potent CYP3A4 inhibitor, coadministration of other substrates of CYP3A4 with darunavir/ritonavir requires caution or is even contraindicated. Guidance is derived from drug-drug interaction trials and experience from comparable ritonavir-boosted protease inhibitor regimens.

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

Palella Jr FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998; 338(13): 853–60PubMedCrossRef

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): 725–33PubMedCrossRef

Surleraux DL, Tahri A, Verschueren WG, et al. Discovery and selection of TMC114, a next generation HIV-1 protease inhibitor. J Med Chem 2005; 48(6): 1813–22PubMedCrossRef

De Meyer S, Azijn H, Surleraux D, et al. TMC114, a novel human immunodeficiency virus type 1 protease inhibitor active against protease inhibitor-resistant viruses, including a broad range of clinical isolates. Antimicrob Agents Chemother 2005; 49(6): 2314–21PubMedCrossRef

King NM, Prabu-Jeyabalan M, Nalivaika EA, et al. Structural and thermodynamic basis for the binding of TMC114, a next-generation human immunodeficiency virus type 1 protease inhibitor. J Virol 2004; 78(21): 12012–21PubMedCrossRef

Clotet B, Bellos N, Molina JM, et al. Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomized trials. Lancet 2007 Apr 7; 369(9568): 1169–78PubMedCrossRef

Katlama C, Esposito R, Gatell JM, et al. Efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients: 24-week result of POWER 1. AIDS 2007 Feb 19; 21(4): 395–402PubMedCrossRef

Haubrich R, Berger D, Chiliade P, et al. Week 24 efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients. AIDS 2007 Mar 30; 21(6): F11–8PubMedCrossRef

Lefebvre E, De Meyer S, De Paepe E, et al. Darunavir (TMC114)/r provides greater efficacy benefits versus control protease inhibitor(s), regardless of the protease inhibitor or sensitivity to the protease inhibitor: POWER 1 and POWER 2 trials [poster]. 8th International Congress on Drug Therapy in HIV Infection; 2006 Nov 12–16; Glasgow, 29

10.

Tibotec, Inc. PREZISTA™ (darunavir) tablets: full prescribing information [online]. Available from URL: http://www.prezista.com/docs/us_package_insert.pdf [Accessed 2007 Jul 20]

11.

TMC114 investigator’s brochure. 7th ed. Mechelen, Belgium: Tibotec BVBA Drug Development Group, 2006 Mar: 24

12.

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): 1623–7PubMedCrossRef

13.

Sekar V, Spinosa-Guzman S, Lefebvre E, et al. Clinical pharmacology of TMC114: a new HIV protease inhibitor [poster no.TUPE0083]. 16th International AIDS Conference; 2006 Aug 13–18; Toronto

14.

Hoetelmans R, Lefebvre E, van der Sandt I, et al. Pharmacokinetics and effect of food on TMC 114, a potent next generation protease inhibitor, boosted with low-dose ritonavir [poster no. 5.6]. 5th International Workshop on Clinical Pharmacology of HIV Therapy; 2004 Apr 1–3; Rome

15.

Sekar V, Kestens D, Spinosa-Guzman S, et al. The effect of different meal types on the pharmacokinetics of darunavir (TMC114)/ritonavir in HIV-negative healthy volunteers. J Clin Pharmacol 2007 Apr; 47(4): 479–84PubMedCrossRef

16.

Boffito M, Acosta E, Burger D, et al. Current status and future prospects of therapeutic drug monitoring and applied clinical pharmacology in antiretroviral therapy. Antivir Ther 2005; 10(3): 375–92PubMed

17.

Sekar V, Guzman S, Stevens T, et al. Absolute bioavailability of TMC114, administered in the absence and presence of low-dose ritonavir [poster]. 7th International Workshop on Pharmacology of HIV Therapy; 2006 Apr 20–22; Lisbon, 86

18.

TMC114 investigator’s brochure. 7th ed. Mechelen, Belgium: Tibotec BVBA Drug Development Group, 2006 Mar: 27

19.

TMC114 investigator’s brochure. 7th ed. Mechelen, Belgium: Tibotec BVBA Drug Development Group, 2006 Mar: 29

20.

Sekar V, Spinosa-Guzman S, Lasure A, et al. Mass-balance study of ¹⁴C-labelled darunavir (TMC114) in HIV-negative healthy volunteers [poster no. 80]. 8th International Workshop on Clinical Pharmacology of HIV Therapy; 2007 Apr 16–18; Budapest

21.

TMC114 investigator’s brochure. 7th ed. Mechelen, Belgium: Tibotec BVBA Drug Development Group, 2006 Mar: 32

22.

TMC114 investigator’s brochure. 7th ed. Mechelen, Belgium: Tibotec BVBA Drug Development Group, 2006 Mar: 44

23.

Zeldin RK, Petruschke RA. Pharmacological and therapeutic properties of ritonavir-boosted protease inhibitor therapy in HIV-infected patients. J Antimicrob Chemother 2004; 53(1): 4–9PubMedCrossRef

24.

Hoetelmans R, Van der Sandt I, De Pauw M, et al. TMC114, a next generation HIV protease inhibitor: pharmacokinetics and safety following oral administration of multiple doses with and without low doses of ritonavir in healthy volunteers [poster/abstract no. 549]. 10th Conference on Retroviruses and Opportunistic Infections; 2003 Feb 10–14; Boston (MA)

25.

Grinsztejn B, Arastéh K, Clotet B, et al. TMC114/r is well tolerated in 3-class-experienced patients: week 24 primary safety analysis of POWER 1 (TMC114-C213) [poster no. WePeLB6.201]. 3rd IAS Conference on HIV Pathogenesis and Treatment; 2005 Jul 24–27; Rio de Janeiro

26.

Molina JM, Cohen C, Katlama C, et al. Safety and efficacy of darunavir (TMC114) with low-dose ritonavir in treatmentexperienced patients: 24-week results of POWER 3. J Acquir Immune Defic Syndr. Epub 2007 Jul 5

27.

Sekar V, De Meyer S, Vangeneugden T, et al. Pharmacokinetic/pharmacodynamic (PK/PD) analyses of TMC114 in the POWER 1 and POWER 2 trials in treatment-experienced HIV-infected patients [poster/abstract no. J-121]. 13th Conference on Retroviruses and Opportunistic Infections (CROI); 2006 Feb 5–8; Denver (CO)

28.

Sekar V, De Meyer, Vangeneugden T, et al. Absence of TMC114 exposure-efficacy and exposure-safety relationships in POWER 3 [poster no. TUPE0078]. 16th International AIDS Conference; 2006 Aug 13–18; Toronto

29.

Collier AC, Goffard JC, Katner H, et al. Safety and efficacy of TMC114/r (darunavir/ritonavir) by gender, age and race: combined 24-week analysis of POWER 1, 2 and 3 [poster no. H-1396]. 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2006 Sep 27–30; San Francisco (CA)

30.

Sekar V, De Marez T, Spinosa-Guzman S, et al. Pharmacokinetic interaction between TMC114/ritonavir and atazanavir in healthy volunteers [poster no. PE4.3/4]. 10th European AIDS Conference; 2005 Nov 17–20; Dublin

31.

Sekar V, Lefebvre E, De Marez T, et al. Pharmacokinetic interaction between the HIV protease inhibitors TMC114 and indinavir in the presence of low-dose ritonavir [poster no. 4.15]. International Symposium on HIV and Emerging Infectious Diseases; 2006 Jun 21–23; Toulon

32.

Sekar V, Lefebvre E, Spinosa-Guzman S, et al. Pharmacokinetic interaction between the protease inhibitors TMC114 and lopinavir/ritonavir [poster no. A-0367]. 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2006 Sep 27–30; San Francisco (CA)

33.

Sekar V, Lefebvre E, Mariën K, et al. Pharmacokinetic interaction between the HIV protease inhibitors TMC114 and saquinavir, in the presence of low-dose ritonavir [poster no. 959]. 44th Annual Meeting of the Infectious Disease Society of America; 2006 Oct 12–15; Toronto

34.

Mouly S, Lown KS, Kornhauser D, et al. Hepatic but not intestinal CYP3A4 displays dose-dependent induction by efavirenz in humans. Clin Pharmacol Ther 2002; 72(1): 1–9PubMedCrossRef

35.

Hariparsad N, Nallani SC, Sane RS, et al. Induction of CYP3A4 by efavirenz in primary human hepatocytes: comparison with rifampin and phenobarbital. J Clin Pharmacol 2004; 44(11): 1273–81PubMedCrossRef

36.

Hsu A, Isaacson J, Bran 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: 350–9PubMedCrossRef

37.

Preston S, Piliero P, O’Mara E, et al. Evaluation of the steadystate interaction between atazanavir (ATV) and efavirenz (EFV) [abstract no. 443]. 9th Conference on Retroviruses and Opportunistic Infections; 2002 Feb 24–28; Seattle (WA)

38.

Sekar V, De Pauw M, Mariën K, et al. No clinically significant pharmacokinetic drug-drug interaction is observed between the HIV protease inhibitor TMC114 and the non-nucleoside reverse transcriptase inhibitor efavirenz [poster no. 55]. 7th International Workshop on Clinical Pharmacology of HIV Therapy; 2006 Apr 20–22; Lisbon

39.

Erickson DA, Mather G, Trager WF, et al. Characterization of the in vitro biotransformation of the HIV-1 reverse transcriptase inhibitor nevirapine by human hepatic cytochromes P-450. Drug Metab Dispos 1999; 27: 1488–95PubMed

40.

Sekar VJ, Lefebvre E, Mariën K, et al. Pharmacokinetic interaction between the antiretroviral agents TMC114 and nevirapine, in the presence of low-dose ritonavir [poster/abstract no. 956]. 44th Annual Meeting of the Infectious Disease Society of America; 2006 Oct 12–15; Toronto

41.

Boffito M, Winston A, Fletcher C, et al. Pharmacokinetics (PK) and antiretroviral (ARV) response to TMC114/r and TMC125 combination in patients with high level resistance [poster no. 575c]. 13th Conference on Retroviruses and Opportunistic Infections (CROI); 2006 Feb 5–8; Denver (CO)

42.

Boffito M, Winston A, Jackson A, et al. Pharmacokinetics and antiretroviral response to darunavir/ritonavir and etravirine combination in patients with high-level viral resistance. AIDS 2007 Jul 11; 21(11): 1449–55PubMedCrossRef

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.

Kearney BP, Mathias A, Mittan A, et al. Pharmacokinetics and safety of tenofovir disoproxil fumarate on coadministration with lopinavir/ritonavir. J Acquir Immune Defic Syndr 2006; 43(3): 278–83PubMedCrossRef

45.

Hoetelmans R, Mariën K, De Pauw M, et al. Pharmakokinetic interaction between TMC114/ritonavir and tenofovir disoproxil fumarate in healthy volunteers. Br J Clin Pharmacol. Epub 2007 Jul 4

46.

Sekar V, De Paepe E, Vangeneugden T, et al. Absence of an interaction between the potent HIV protease inhibitor TMC114 and the fusion inhibitor enfuvirtide in the POWER 3 analysis [poster no. P54]. 7th International Workshop on Clinical Pharmacology of HIV Therapy; 2006 Apr 20–22; Lisbon

47.

Abel S, Ridgway C, Hamlin J, et al. An open, randomized, 2-way crossover study to investigate the effect of darunavir/ritonavir on the pharmacokinetics of maraviroc in healthy subjects [poster/abstract no. 55]. 8th International Workshop on Clinical Pharmacology of HIV Therapy; 2007 Apr 16–18; Budapest

48.

Muirhead G, Pozniak A, Boffito M, et al. A novel probe drug interaction study to investigate the effect of selected ARV combinations on the pharmacokinetics of a single oral dose of maraviroc (UK-427,857) in HIV+ve subjects [poster no. 2.19]. 6th International Workshop on Clinical Pharmacology of HIV Therapy; 2005 Apr 28–30; Quebec City

49.

Bernini F, Poli A, Paoletti R. Safety of HMG-CoA reductase inhibitors: focus on atorvastatin. Cardiovasc Drugs Ther 2001; 15(3): 211–8PubMedCrossRef

50.

Hsyu PH, Schultz-Smith MD, Lillibridge JH, et al. Pharmacokinetic interactions between nelfinavir and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and simvastatin. Antimicrob Agents Chemother 2001; 45(12): 3445–50PubMedCrossRef

51.

Fichtenbaum CJ, Gerber JG. Interactions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encountered during HIV infection. Clin Pharmacokinet 2002; 41(14): 1195–211PubMedCrossRef

52.

Chuck SK, Penzak SR. Risk-benefit of HMG-CoA reductase inhibitors in the treatment of HIV protease inhibitor-related hyperlipidaemia. Expert Opin Drug Saf 2002; 1(1): 5–17PubMedCrossRef

53.

Hoetelmans R, Lasure A, Koester A, et al. The effect of TMC114, a potent next-generation HIV protease inhibitor, with low-dose ritonavir on atorvastatin pharmacokinetics [poster no. H-865]. 44th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2004 Oct 30–Nov 2; Washington, DC

54.

Sekar V, Spinosa-Guzman S, De Pauw M, et al. The pharmacokinetic interaction between clarithromycin and TMC114/ritonavir in healthy subjects [poster no. PI-61]. 2006 Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics; 2006 Mar 8–11; Baltimore (MD)

55.

Sekar V, Lefebvre E, Spinosa-Guzman S, et al. Pharmacokinetic interaction between ethinyl estradiol, norethindrome and TMC114, a new protease inhibitor [poster no. A-0368]. 46th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2006 Sep 27–30; San Francisco (CA)

56.

Sekar V, Lefebvre E, De Pauw M, et al. Pharmacokinetic interaction between TMC114 and ketoconazole, in the absence and presence of low-dose ritonavir [poster/abstract no. 960]. IDSA 44th Annual Meeting; 2006 Oct 12–15; Toronto

57.

Eap CB, Bourquin M, Martin J, et al. Plasma concentrations of the enantiomers of methadone and therapeutic response in methadone maintenance treatment. Drug Alcohol Depend 2000; 61(1): 47–54PubMedCrossRef

58.

McCance-Katz EF, Rainey PM, Friedland G, et al. The protease inhibitor lopinavir-ritonavir may produce opiate withdrawal in methadone-maintained patients. Clin Infect Dis 2003; 37(4): 476–82PubMedCrossRef

59.

Sekar V, El Malt M, De Paepe E, et al. Pharmacokinetic interaction between darunavir (TMC114), a new protease inhibitor and methadone [poster no. P294]. 8th International Congress on Drug Therapy in HIV Infection; 2006 Nov 12–16; Glasgow

60.

Sekar VJ, Lefebvre E, De Paepe E, et al. Pharmacokinetic interaction between darunavir boosted with ritonavir and omeprazole or ranitidine in human immunodeficiency virusnegative healthy volunteers. Antimicrob Agents Chemother 2007 Mar; 51(3): 958–61PubMedCrossRef

61.

Pfizer Inc. ZOLOFT® (sertraline hydrochloride) tablets and oral concentrate: prescribing information [online]. Available from URL: http://www.pfizer.com/pfizer/download/uspi_zoloft.pdf [Accessed 2007 Jul 20]

62.

GlaxoSmithKline. PAXIL® (paroxetine hydrochloride) tablets and oral suspension: prescribing information [online]. Available from URL: http://us.gsk.com/products/assets/us_paxil.pdf [Accessed 2007 Jul 20]

63.

Sekar V, De Paepe E, De Marez T, et al. Pharmacokinetic interaction between darunavir (TMC114), a new protease inhibitor, and the selective serotonin reuptake inhibitors (SSRIs), paroxetin and sertraline [poster no. P295]. 8th International Congress on Drug Therapy in HIV Infection; 2006 Nov 12–16; Glasgow

64.

Tasker TC, Kaye CM, Zussman BD, et al. Paroxetine plasma levels: lack of correlation with efficacy or adverse events. Acta Psychiatr Scand Suppl 1989; 350: 152–5PubMedCrossRef

65.

Preskorn SH, Lane RM. Sertraline 50mg daily: the optimal dose in the treatment of depression. Int Clin Psychopharmacol 1995; 10(3): 129–41PubMedCrossRef

66.

Pfizer Inc. VIAGRA® (sildenafil citrate) tablets: prescribing information [online]. Available from URL: http://pfizer.com/pfizer/download/uspi_viagra.pdf [Accessed 2007 Jul 20]

67.

Sekar V, Lefebvre E, De Marez T, et al. Pharmacokinetic interaction between TMC114, a new protease inhibitor and sildenafil [poster no. A-0369]. 46th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; 2006 Sep 27–30; San Francisco (CA)

Titel: Clinical Pharmacokinetics of Darunavir
verfasst von: Michael Rittweger
PD Dr. med. Keikawus Arastéh
Publikationsdatum: 01.09.2007
Verlag: Springer International Publishing
Erschienen in: Clinical Pharmacokinetics / Ausgabe 9/2007
Print ISSN: 0312-5963
Elektronische ISSN: 1179-1926
DOI: https://doi.org/10.2165/00003088-200746090-00002

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 9/2007

The Authors′ Reply

Integrated Pharmacokinetics and Pharmacodynamics in Drug Development

Pharmacokinetics and Tolerability of Duloxetine following Oral Administration to Healthy Chinese Subjects

Increased Absorption of Digoxin from the Human Jejunum Due to Inhibition of Intestinal Transporter-Mediated Efflux

The Absolute Oral Bioavailability and Population-Based Pharmacokinetic Modelling of a Novel Dipeptidylpeptidase-IV Inhibitor, Vildagliptin, in Healthy Volunteers

Phase I Evaluation of the Safety, Pharmacokinetics and Pharmacodynamics of CP-481,715