Vicriviroc, a new CC-chemokine receptor 5 inhibitor for treatment of HIV: Properties, promises and challenges

Expert Opinion on Drug Metabolism and Toxicology

Volumn 6, Issue 9, 2010, Pages 1139-1150

  Lenz, Johannes Carl Christoph ^a   Rockstroh, Jrgen Kurt ^a  

^a UNIVERSITY OF BONN   (Germany)

Author keywords

Antiretroviral therapy; CCR5 antagonist; HIV; Tropism testing; Vicriviroc

Indexed keywords

ATAZANAVIR; CARBAMAZEPINE; CHEMOKINE RECEPTOR CCR5 ANTAGONIST; DARUNAVIR; EFAVIRENZ; ETHINYLESTRADIOL; FOSAMPRENAVIR; INDINAVIR; KETOCONAZOLE; LAMIVUDINE PLUS ZIDOVUDINE; LOPINAVIR; MIDAZOLAM; NELFINAVIR; NORETHISTERONE; PLACEBO; PROTEINASE INHIBITOR; RIFABUTIN; RIFAMPICIN; RITONAVIR; SAQUINAVIR; TENOFOVIR; VICRIVIROC;

ABDOMINAL PAIN; ADD ON THERAPY; ANOREXIA; CLINICAL TRIAL; DIARRHEA; DIZZINESS; DRUG ELIMINATION; DRUG INDUCED HEADACHE; DRUG METABOLISM; DRUG SAFETY; DRUG TOLERABILITY; FATIGUE; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS 1 INFECTION; HUMAN IMMUNODEFICIENCY VIRUS INFECTED PATIENT; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; MEDLINE; NAUSEA; NONHUMAN; PHARMACODYNAMICS; REVIEW; RHINOPHARYNGITIS; SYSTEMATIC REVIEW; VOMITING;

ANTI-HIV AGENTS; CLINICAL TRIALS AS TOPIC; COMORBIDITY; DRUG INTERACTIONS; DRUG RESISTANCE, VIRAL; FEMALE; HEPATITIS C; HIV INFECTIONS; HIV-1; HUMANS; MALE; PIPERAZINES; PYRIMIDINES; RECEPTORS, CCR5;

HUMAN IMMUNODEFICIENCY VIRUS 1;

EID: 77955785228     PISSN: 17425255     EISSN: None     Source Type: Journal    
DOI: 10.1517/17425255.2010.510833     Document Type: Review

References (59)

1. El-Sadr WM, Lundgren JD, Neaton JD, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006;355:2283-2296
2. Fatkenheuer G, Nelson M, Lazzarin A, et al. MOTIVATE 1 and MOTIVATE 2 Study Teams. Subgroup analyses of maraviroc in previously treated R5 HIV-1 infection. N Engl J Med 2008;359:1442-1455
3. Wilken T, Lalama C, McKinnon J, et al. Maraviroc intensification for suboptimal CD4+ cell response despite sustained virologic suppression: ACTG 5256 [abstract 285]. 17th CROI
4. Berger EA, Murphy PM, Farber JM. Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu Rev Immunol 1999;17:657-700
5. Tagat JR, McCombie SW, Nazareno D, et al. Piperazine-based CCR5 antagonists as HIV-1 inhibitors. IV. Discovery of 1-[(4,6-dimethyl-5- pyrimidinyl)carbonyl]- 4-[4-(2-methoxy-1(R)-4-trifluoromethyl)- phenyl)ethyl-3(S)-methyl-1-piperazinyl]- 4-methylpiperidine (Sch-417690/Sch-D), a potent, highly selective, and orally bioavailable CCR5 antagonist. J Med Chem 2004;47:2405-2408
6. Sattentau QJ, Moore JP. Conformational changes induced in the human immunodeficiency virus envelope glycoprotein by soluble CD4 binding. J Exp Med 1991;174:407-415
7. Trkola A, Dragic T, Arthos J, et al. CD4- dependent, antibody-sensitive interactions between HIV-1 and its co-receptor CCR-5. Nature 1996;384:184-187
8. Wu L, Gerard NP, Wyatt R, et al. CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5. Nature 1996;384:179-183
9. Chan DC, Fass D, Berger JM, Kim PS. Core structure of gp41 from the HIV envelope glycoprotein. Cell 1997;89:263-273
10. Chan DC, Kim PS. HIV entry and its inhibition. Cell 1998;93:681-684
11. Huang CC, Lam SN, Acharya P, et al. Structures of the CCR5 N terminus and of a tyrosine-sulfated antibody with HIV-1 gp120 and CD4. Science 2007;317:1930-1934
12. Huang CC, Tang M, Zhang MY, et al. Structure of a V3-containing HIV-1 gp120 core. Science 2005;310:1025-1028
13. Rizzuto C, Sodroski J. Fine definition of a conserved CCR5-binding region on the human immunodeficiency virus type 1 glycoprotein 120. AIDS Res Hum Retroviruses 2000;16:741-749
14. Rizzuto C, Wyatt R, Hernandez-Ramos N, et al. A conserved HIV gp120 glycoprotein structure involved in chemokine receptor binding. Science 1998;280:1949-1953
15. Wyatt R, Kwong PD, Desjardins E, et al. The antigenic structure of the HIV gp120 envelope glycoprotein. Nature 1998;393:705-711
16. Dragic T, Trkola A, Thompson DA, et al. A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5. Proc Natl Acad Sci USA 2000;97:5639-5644
17. Kondru R, Zhang J, Ji C, et al. Molecular interactions of CCR5 with major classes of small-molecule anti-HIV CCR5 antagonists. Mol Pharmacol 2008;73:789-800
18. Maeda K, Das D, Ogata-Aoki H, et al. Structural and molecular interactions of CCR5 inhibitors with CCR5. J Biol Chem 2006;281:12688-12698
19. Tsamis F, Gavrilov S, Kajumo F, et al. Analysis of the mechanism by which the small-molecule CCR5 antagonists SCH-351125 and SCH-350581 inhibit human immunodeficiency virus type 1 entry. J Virol 2003;77:5201-5208
20. Berger EA, Murphy PM, Farber JM. Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism and disease. Annu Rev Immunol 1999;17:657-700
21. Lederman MM, Penn-Nicholson A, Cho M, Mosier D. Biology of CCR5 and its role in HIV infection and treatment. JAMA 2006;296:815-826
22. Lusso P. HIV and the chemokine system: 10 years later. EMBO J 2006;25:447-456
23. Schurmann D, Fatkenheuer G, Reynes J, et al. Antiviral activity, pharmacokinetics and safety of vicriviroc, an oral CCR5 antagonist, during 14-day monotherapy in HIV-infected adults. AIDS 2007;21:1293-1299
24. Sansone A, Keung A, Caceres M, et al. Rising multiple-dose assessment of Sch 417690 - Similar safety, tolerability, and pharmacokinetics (PK) in uninfected and HIV-infected adults [abstract A-33]. 45th ICAAC 2005
25. Keung A, Sansone A, Caceres M, et al. Effect of food on bioavailability of Sch 417690 in healthy volunteers [abstract A-1200]. 45th ICAAC 2005
26. Crawford KW, Li C, Keung A, et al. Pharmacokinetic/pharmacodynamic modeling of the antiretroviral activity of the CCR5 antagonist vicriviroc in treatment experienced HIV-infected subjects (ACTG protocol 5211). J Acquir Immune Defic Syndr 2010;53:598-605
27. Ghosal A, Ramanathan R, Yuan Y, et al. Identification of human liver cytochrome P450 enzymes involved in biotransformation of vicriviroc, a CCR5 receptor antagonist. Drug Metab Dispos 2007;35:2186-2195
28. Ghosal A, Barecki-Roach M, Ramanathan R, et al. Characterization of the in vitro human liver cytochrome P450 (CYP) mediated metabolism and inhibition potential of vicriviroc. Retrovirology 2005;2(Suppl 1):abstract P116
29. Ramanathan R, Zhong R, Alvarez N, et al. Comparative metabolism and excretion of a novel CCR5 receptor antagonist, Sch 417690 (vicriviroc), in human, monkey and rat. Drug Metab Rev 2005;37:725-726
30. Ikezoe T, Hisatake Y, Takeuchi T, et al. HIV-1 protease inhibitor, ritonavir: a potent inhibitor of CYP3A4, enhanced the anticancer effects of docetaxel in androgen-independent prostate cancer cells in vitro and in vivo. Cancer Res 2004;64:7426-7431
31. Seiberling M, Kraan M, Keung A, et al. Similar increase in vicriviroc exposure with co-administration of varying doses of ritonavir in healthy volunteers [abstract TUPE3.1B06]. 3rd IAS Conference on HIV Pathogenesis and Treatment; 2005
32. Sansone A, Keung A, Tetteh E, et al. Vicriviroc (VCV) pharmacokinetics (PK): lack of impact of ritonavir (RTV)-boosted protease inhibitors (PI) [abstract TUPE0074]. XVI International AIDS Conference; 2006
33. Kasserra C, Sansone-Parsons A, Keung A, et al. Vicriviroc pharmacokinetic parameters are unchanged when co-administered with darunavir in a ritonavir containing regimen [abstract P35]. 9th annual International Workshop on Clinical Pharmacology of HIV Therapy; 2008
34. Saltzman M, Rosenberg M, Kraan M, et al. Pharmacokinetics of SCH 417690 administered alone or in combination with ritonavir or lopinavir/ritonavir [abstract TUPE3.1B05]. 3rd IAS Conference on HIV Pathogenesis and Treatment; 2005
35. Guillaume M, Kraan M, Keung A, et al. The pharmacokinetics of SCH 417690 when administered alone and in combination with lamivudine/zidovudine [abstract TUPE3.1B03]. 3rd IAS Conference on HIV Pathogenesis and Treatment; 2005
36. Guillaume M, Kraan M, Soni P, et al. Pharmacokinetics of SCH 417690 administered alone or in combination with tenofovir [abstract TUPE3.1B09]. 3rd IAS Conference on HIV Pathogenesis and Treatment; 2005
37. Brown KC, Paul S, Kashuba AD. Drug interactions with new and investigational antiretrovirals. Clin Pharmacokinet 2009;48:211-241
38. Saltzman M, Rosenberg M, Kraan M, et al. Pharmacokinetics of SCH 417690 administered alone or in combination with ritonavir and efavirenz in healthy volunteers [abstract TUPE3.1B08]. 3rd IAS Conference on HIV Pathogenesis and Treatment; 2005
39. Kasserra C, Adamczyk R, Li J, et al. The effect of vicriviroc with or without ritonavir on oral contraceptive pharmacokinetics [abstract TUPE0043]. XVII International AIDS Conference; 2008
40. Kasserra C, O'Mara E, Lisbon E. Assessment of pharmacokinetic and safety interactions between vicriviroc and CYP3A4 substrates, inhibitors, and inducers [abstract H-230]. 49th ICAAC 2009
41. Landovitz RJ, Angel JB, Hoffmann C, et al. Phase II study of vicriviroc versus efavirenz (both with zidovudine/lamivudine) in treatment-naive subjects with HIV-1 infection. J Infect Dis 2008;198:1113-1122
42. McNicholas P, Wei Y, Whitcomb J, et al. Characterization of emergent HIV resistance in treatment-naive subjects enrolled in a vicriviroc phase 2 trial. J Infect Dis 2010;201:1470-1480
43. Gulick RM, Su Z, Flexner C, et al. Phase 2 study of the safety and efficacy of vicriviroc, a CCR5 inhibitor, in HIV-1-Infected, treatment-experienced patients: AIDS clinical trials group 5211. J Infect Dis 2007;196:304-312
44. Su Z, Gulick RM, Krambrink A, et al. Response to vicriviroc in treatment-experienced subjects, as determined by an enhanced-sensitivity coreceptor tropism assay: reanalysis of AIDS clinical trials group A5211. J Infect Dis 2009;200:1724-1728
45. Tsibris AM, Korber B, Arnaout R, et al. Quantitative deep sequencing reveals dynamic HIV-1 escape and large population shifts during CCR5 antagonist therapy in vivo. PLoS One 2009;4:e5683
46. Tsibris AM, Sagar M, Gulick RM, et al. In vivo emergence of vicriviroc resistance in a human immunodeficiency virus type 1 subtype C-infected subject. J Virol 2008;82:8210-8214
47. Suleiman J, Zingman BS, Diaz RS, et al. Vicriviroc in combination therapy with an optimized regimen for treatment-experienced subjects: 48-week results of the VICTOR-E1 phase 2 trial. J Infect Dis 2010;201(4):590-599
48. Gathe J, Diaz R, Fatkenheuer G, et al. Phase 3 trials of vicriviroc in treatment-experienced subjects demonstrate safety but not significantly superior efficacy over potent background regimens alone [abstract 54LB]. 17th CROI 2010
49. Efficacy and Safety of VICRIVIROC in HIV-Infected Treatment-Naive Subjects (Study P04875AM5) Available from: ct2/show/NCT00551018 [Last accessed 26 April 2010]
50. Moore JP, Kuritzkes DR. A piece de resistance: how HIV-1 escapes small molecule CCR5 inhibitors. Curr Opin HIV AIDS 2009;4:118-124
51. O'Mara E, Kasserra C, Huddlestone JR, et al. The effect of vicriviroc on the QT/QTc interval and central nervous system in healthy subjects. Antimicrob Agents Chemother 2010: published online 29 March 2010, doi:10.1128/AAC.01447-09
52. Gulick R, Haas D, Collier AC, et al. Two-year follow-up of treatment-experienced patients on vicriviroc (VCV) [abstract H-1030]. 47th Interscience ICAAC 2007
53. Dunkle LM, Greaves W, McCarthy MC, et al. Long term safety of vicriviroc [abstract H-1269]. 48th ICAAC 2008
54. Fatkenheuer G, Hoffmann C, Slim J, et al. Short-term administration of the CCR5 antagonist vicriviroc to patients with HIV and HCV coinfection is safe and tolerable. J Acquir Immune Defic Syndr 2010;53:78-85
55. Kasserra C, Sansone-Parsons A, Keung A, et al. Renal insufficiency has no effect on the pharmacokinetics of vicriviroc in a ritonavir-containing regimen. Clin Pharmacokinet 2010: published online 1 June 2010, doi:10.2165/ 11319470-000000000-00000
56. Safety and Immune Response to Vicriviroc in Combination Regimens in HIV-Infected Antiretroviral Treatment Experienced Children and Adolescents. Available from: http://clinicaltrials.gov/ct2/results?term=NCT00766597 [Last accessed 14 July 2010]
57. UPDATE 2-Merck HIV drug from Schering merger fails trails. Available from: idUSN2017965820100120
58. Hunt PW, Brenchley J, Sinclair E, et al. Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis 2008;197(1):126-133
59. Hunt PW, Martin JN, Sinclair E, et al. T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. J Infect Dis 2003;187(10):1534-1543