Darunavir (TMC114) is a new HIV protease inhibitor that has demonstrated substantial antiretroviral activity against wild-type HIV-1 virus and multidrug-resistant strains. Darunavir inhibits and is primarily metabolized by cytochrome P450 3A (CYP3A) isoenzymes and is coadministered with low-dose ritonavir (darunavir/r); ritonavir is an inhibitor of CYP3A isoenzymes and pharmacologically enhances darunavir, resulting in increased plasma concentrations and allowing for a lower daily dose. The t1/2 (terminal elimination half-life) of darunavir is 15 h in the presence of ritonavir. An extensive darunavir/r drug-drug interaction programme has been undertaken, covering a wide range of therapeutic areas. Studies conducted in HIV-negative healthy volunteers and in HIV-infected patients show that the potential for interactions is well characterized and the interactions are manageable. For most drugs investigated, no dose adjustments of darunavir/r or the co-administered drug are required. This article reviews all the pharmacokinetic and drug-drug interaction studies conducted to date for darunavir/r, providing guidance on how to co-administer darunavir/r with many other antiretroviral or non-antiretroviral medications commonly used in HIV-infected individuals.
References
1.
US Department of Health and Human Services (DHHS).Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. October 2006. [Updated Dec 2006; accessed 19 Jan 2007]. Available from: http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
2.
De MeyerS., AzijnH., SurlerauxD.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 Chemother2005; 49: 2314–2321.
3.
KohY., NakataH., MaedaK.Novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI) UIC-94017 (TMC114) with potent activity against multi-PI-resistant human immunodeficiency virus in vitro.Antimicrob Agents Chemother2003; 47: 3123–3129.
HaubrichR.H., BergerD., ChiliadeP.Week 24 efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients.AIDS2007; 21: F11–F18.
6.
KatlamaC., EspositoR., GatellJ.M.Efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients: 24-week results of POWER 1.AIDS2007; 21: 395–402.
7.
MolinaJ., CohenC., KatlamaC.Safety and efficacy of darunavir (TMC114) with low-dose ritonavir in treatment-experienced patients: 24-week results of POWER 3.J Acquir Immune Defic Syndr2007; 46: 24–31.
8.
ClotetB., BellosN., MolinaJ.M.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.Lancet2007; 369: 1169–1178.
9.
SurlerauxD.L., TahriA., VerschuerenW.G.Discovery and selection of TMC114, a next generation HIV-1 protease inhibitor.J Med Chem2005; 48: 1813–1822.
10.
TieY., BorossP.I., WangY.F.High resolution crystal structures of HIV-1 protease with a potent non-peptide inhibitor (UIC-94017) active against multi-drug-resistant clinical strains.J Mol Biol2004; 338: 341–352.
11.
KingN.M., Prabu-JeyabalanM., NalivaikaE.A.Structural and thermodynamic basis for the binding of TMC114, a next-generation human immunodeficiency virus type 1 protease inhibitor.J Virol2004; 78: 12012–12021.
12.
SekarV., El MaltM., De PaepeE.Effect of the HIV protease inhibitor darunavir (TMC114), coadministered with low-dose ritonavir, on the pharmacokinetics of digoxin in healthy volunteers.The Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics. March 21–24 2007, Anaheim, CA, USA. Abstract PII-104.
13.
SekarV., Spinosa-GuzmanS., LefebvreE., HoetelmansR.Clinical pharmacology of TMC114 - a new HIV protease inhibitor.The 16th International AIDS Conference. 13–18 August 2006, Toronto, Canada. Abstract TUPE0083.
14.
SchonA., del Mar IngaramoM., FreireE.The binding of HIV-1 protease inhibitors to human serum proteins.Biophys Chem2003; 105: 221–230.
SekarV., GuzmanS., StevensT.Absolute bioavailability of TMC114, administered in the absence and presence of low-dose ritonavir.The 7th International Workshop on Clinical Pharmacology of HIV Therapy. 20–22 April 2006, Lisbon, Portugal. Abstract P86.
17.
SekarV., KestensD., Spinosa-GuzmanS.The effect of different meal types on the pharmacokinetics of darunavir (TMC114)/ritonavir in HIV-negative healthy volunteers.J Clin Pharmacol2007; 47: 479–484.
18.
BoffitoM., AcostaE., BurgerD.Current status and future prospects of therapeutic drug monitoring and applied clinical pharmacology in antiretroviral therapy.Antivir Ther2005; 10: 375–392.
19.
FurlerM.D., EinarsonT.R., WalmsleyS., MillsonM., BendayanR.Polypharmacy in HIV: impact of data source and gender on reported drug utilization.AIDS Patient Care STDS2004; 18: 568–586.
20.
BackD., SekarV., LefebvreE.Use of darunavir (TMC114) in combination with other drugs: guidance from pharmacokinetic studies.8th International Congress on Drug Therapy in HIV Infection. 12–16 November 2006, Glasgow, UK. Abstract PL5.1.
21.
SekarV.J., LefebvreE., DeM.T.Pharmacokinetics of darunavir (TMC114) and atazanavir during coadministration in HIV-negative, healthy volunteers.Drugs R D2007; 8: 241–248.
22.
SekarV., LefebvreE., De MarezT.Pharmacokinetic interaction between the HIV protease inhibitors TMC114 and indinavir in the presence of low-dose ritonavir.The International Symposium on HIV and Emerging Infectious Diseases. June 21–23 2006, Toulon, France. Abstract PP4.15.
23.
SekarV., LefebvreE., Spinosa-GuzmanS.Pharmacokinetic interaction between the protease inhibitors TMC114 and lopinavir/ritonavir.46th Interscience Conference on Antimicrobial Agents and Chemotherapy. 27–30 September 2006, San Francisco, CA, USA. Abstract A-0367.
24.
SekarV., LefebvreE., MarienK.Pharmacokinetic interaction between the HIV protease inhibitors TMC114 and saquinavir, in the presence of low-dose ritonavir.44th Annual Meeting of the Infectious Diseases Society of America. 12–15 October 2006, Toronto, Ontario, Canada. Abstract 959.
25.
HoetelmansR., MarienK., De PauwM.Pharmacokinetic interaction between TMC114/ritonavir and tenofovir disoproxil fumarate in healthy volunteers.Br J Clin Pharmacol2007; 64: 665–661.
26.
SekarV.J., Spinosa-GuzmanS., De PaepeE.Pharmacokinetic interaction trial between darunavir in combination with low-dose ritonavir and didanosine.4th IAS Confernce on HIV Pathogenesis, Treatment and Prevention. Sydney, Australia. 22–25 July 2007. Poster WEPEB012.
27.
SekarV., De PauwM., MarienK.Pharmacokinetic interaction between TMC114/r and efavirenz in healthy volunteers.Antivir Ther2007; 12: 509–514.
28.
SekarV., LefebvreE., MarienK.Pharmacokinetic interaction between the antiretroviral agents TMC114 and nevirapine, in the presence of low-dose ritonavir.44th Annual Meeting of the Infectious Diseases Society of America. 12–15 October 2006, Toronto, Ontario, Canada. Poster 956.
29.
Schöller-GyüreM., KakudaT., SekarV.Pharmacokinetics of darunavir/ritonavir (DRV/r) and TMC125 alone and co-administered in HIV-negative volunteers.Antivir Ther2007; 12: 789–796.
30.
SekarV., De PaepeE., VangeneugdenT.Absence of an interaction between the potent HIV protease inhibitor TMC114 and the fusion inhibitor enfuvirtide in the POWER 3 analysis.7th International Workshop on Clinical Pharmacology of HIV Therapy. 20–22 April 2006, Lisbon, Portugal. Abstract P54.
31.
MathiasA., ShenG., EnejosaJ.Lack of pharmacokinetic interaction between ritonavir-boosted GS-9137 (elvitegravir) and Darunavir/r.4th IAS Confernce on HIV Pathogenesis, Treatment and Prevention. 22–25 July 2007, Sydney, Australia. Abstract TUPDB03.
32.
HoetelmansR., LasureA., KoesterA.The effect on TMC114, a potent next-generation HIV protease inhibitor, with low-dose ritonavir on atorvastatin pharmacokinetics.44th Interscience Conference on Antimicrobial Agents and Chemotherapy. October 30—November 2, 2004, Washington DC, USA. Poster H-865.
33.
SekarV.J., Spinosa-GuzmanS., MarienK.Pharmacokinetic drug-drug interaction between the new HIV protease inhibitor darunavir (TMC114) and the lipid-lowering agent pravastatin.8th International Workshop on Clinical Pharmacology of HIV Therapy. 16–18 April, 2007, Budapest, Hungary. Abstract 54.
34.
SekarV.J., LefebvreE., DeP.E.Pharmacokinetic interaction between TMC114/r and omeprazole or ranitidine in HIV-negative healthy volunteers.Antimicrob Agents Chemother2007; 51: 958–961.
35.
SekarV., El MaltM., De PaepeE.Pharmacokinetic interaction between darunavir (TMC114), a new protease inhibitor, and methadone.8th International Congress on Drug Therapy in HIV Infection. 12–16 November 2006, Glasgow, UK. Abstract P294.
36.
SekarV., LefebvreE., Spinosa-GuzmanS.Pharmacokinetic interaction between ethinyl estradiol, norethindrone and TMC114, a new protease inhibitor.46th Interscience Conference on Antimicrobial Agents and Chemotherapy. September 27–30, 2006, San Francisco, CA, USA. Abstract A-0368.
37.
SekarV., LefebvreE., De MarezT.Pharmacokinetic interaction between TMC114, a new protease inhibitor and sildenafil.46th Interscience Conference on Antimicrobial Agents and Chemotherapy, September 27–30, 2006, San Francisco, CA, USA. Abstract A-0369.
38.
SekarV., De PaepeE., De MarezT.Pharmacokinetic interaction between darunavir (TMC114), a new protease inhibitor, and the selective serotonin reuptake inhibitors (SSRIs), paroxetine and sertraline.8th International Congress on Drug Therapy in HIV Infection. 12–16 November 2006, Glasgow, UK. Abstract P295.
39.
SekarV.J., GuzmanS., De PauwM.The pharmacokinetic interaction between clarithromycin and TMC114/ritonavir in healthy subjects.The 2006 Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics. March 8–11 2006, Baltimore, MD, USA. Abstract PI-61.
40.
SekarV., LefebvreE., De PauwM., VangeneugdenT., HoetelmansR.Pharmacokinetic interaction between TMC114 and ketoconazole, in the absence and presence of low-dose ritonavir.44th Annual Meeting of the Infectious Diseases Society of America. 12–15 October 2006, Toronto, Ontario, Canada. Abstract P960.
41.
SekarV., De MeyerS., VangeneugdenT.Pharmacokinetic/pharmacodynamic (PK/PD) analyses of TMC114 in the POWER 1 and POWER 2 trials in treatment-experienced HIV-infected patients.13th Conference on Retroviruses and Opportunistic Infections. February 5–8 2006, Denver, CO, USA. Abstract J-121.
42.
MalatyL.I., KuperJ.J.Drug interactions of HIV protease inhibitors.Drug Saf1999; 20: 147–169.
43.
HuangL., WringS.A., WoolleyJ.L.Induction of P glycoprotein and cytochrome P450 3A by HIV protease inhibitors.Drug Metab Dispos2001; 29: 754–760.
44.
MollaA., MoH., VasavanondaS.In vitro antiviral interaction of lopinavir with other protease inhibitors.Antimicrob Agents Chemother2002; 46: 2249–2253.
45.
BoffitoM., MoyleG.J.Pharmacokinetic considerations for combining 2 protease inhibitors.The AIDS Reader2004; 14: 110–116.
BackD.J.Drug-drug interactions that matter.Topics in HIV medicine2006; 14: 88–92.
48.
KruseG., EsserS., StockerH.The steady-state pharmacokinetics of nelfinavir in combination with tenofovir in HIV-infected patients.Antivir Ther2005; 10: 349–355.
49.
PikettyC., GerardL., ChazallonC.Salvage therapy with atazanavir/ritonavir combined to tenofovir in HIV-infected patients with multiple treatment failures: randomized ANRS 107 trial.Antivir Ther2006; 11: 213–221.
50.
KearneyB.P., MathiasA., MittanA.Pharmacokinetics and safety of tenofovir disoproxil fumarate on coadministration with lopinavir/ritonavir.J Acquir Immune Defic Syndr2006; 43: 278–283.
51.
RayA.S.Role of intestinal absorption in increased tenofovir exposure when tenofovir disoproxil fumarate is co-administered with atazanavir or lopinavir/ritonavir.7th International Workshop on Clinical Pharmacology of HIV Therapy. 20–22 April 2006, Lisbon, Portugal. Abstract 49.
52.
TrottierB., WalmsleyS., ReynesJ.Safety of enfuvirtide in combination with an optimized background of antiretrovirals in treatment-experienced HIV-1-infected adults over 48 weeks.J Acquir Immune Defic Syndr2005; 40: 413–421.
53.
McCance-KatzE.F., RaineyP.M., FriedlandG., JatlowP.The protease inhibitor lopinavir-ritonavir may produce opiate withdrawal in methadone-maintained patients.Clin Infect Dis2003; 37: 476–482.
54.
AntoniouT., TsengA.L.Interactions between recreational drugs and antiretroviral agents.Ann Pharmacother2002; 36: 1598–1613.
55.
BoffitoM., MaitlandD., PozniakA.Practical perspectives on the use of tipranavir in combination with other medications: lessons learned from pharmacokinetic studies.J Clin Pharmacol2006; 46: 130–139.
56.
RoyP., JakateA.S., PatelA.Effect of multiple-dose dexloxiglumide on the pharmacokinetics of oral contraceptives in healthy women.J Clin Pharmacol2005; 45: 329–336.
57.
HighleymanL.Protease inhibitors and sildenafil (Viagra) should not be combined.BETA1999; 12: 3.
58.
KrikorianS.A., RudorfD.C.Drug-drug interactions and HIV therapy: what should pharmacists know?J Pharm Practice2005; 18: 278–294.
59.
TaskerT.C., KayeC.M., ZussmanB.D., LinkC.G.Paroxetine plasma levels: lack of correlation with efficacy or adverse events.Acta Psychiatr Scand Suppl1989; 350: 152–155.
60.
PreskornS.H., HarveyA.Biochemical and clinical dose-response curves with sertraline.Clin Pharmacol Ther1996; 59: 180.
61.
Abbot Laboratories. Biaxin®XL (clarithromycin) Patient Information [cited 6 February 2007]. Available from: http://www.rxabbott.com/pdf/biapi.PDF. Revised August 2006.
