A randomized, placebo controlled, double masked phase IB study evaluating the safety and antiviral activity of aprepitant, a neurokinin-1 receptor antagonist in HIV-1 infected adults

PLoS ONE

Volumn 6, Issue 9, 2011, Pages

  Tebas, Pablo ^a   Tuluc, Florin ^b   Barrett, Jeffrey S ^b   Wagner, Wayne ^a   Kim, Deborah ^a   Zhao, Huaquing ^c   Gonin, René ^c   Korelitz, James ^c   Douglas, Steven D ^b  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

^b CHILDREN S HOSPITAL OF PHILADELPHIA   (United States)

^c WESTAT   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

APREPITANT; PLACEBO; VIRUS RNA; ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; MORPHOLINE DERIVATIVE; NEUROKININ 1 RECEPTOR;

ADULT; ANTIVIRAL ACTIVITY; AREA UNDER THE CURVE; ARTICLE; CD4 LYMPHOCYTE COUNT; CLINICAL ARTICLE; CONTROLLED STUDY; DIZZINESS; DOSE RESPONSE; DRUG DOSE COMPARISON; DRUG EFFECT; DRUG MECHANISM; DRUG MEGADOSE; DRUG SAFETY; FEMALE; HEADACHE; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1 INFECTION; HYPERSOMNIA; IMMUNOMODULATION; IN VIVO STUDY; INSOMNIA; LOW DRUG DOSE; MALE; MAXIMUM PLASMA CONCENTRATION; NEUROLOGIC DISEASE; OUTCOME ASSESSMENT; PHASE 2 CLINICAL TRIAL; RANDOMIZED CONTROLLED TRIAL; TIME TO MAXIMUM PLASMA CONCENTRATION; VIRAL TROPISM; VIRUS LOAD; CHEMICALLY INDUCED DISORDER; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; DOUBLE BLIND PROCEDURE; DRUG ANTAGONISM; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; METABOLIC CLEARANCE RATE; METABOLISM; MIDDLE AGED; PHASE 1 CLINICAL TRIAL; SOMNOLENCE; TREATMENT OUTCOME;

HUMAN IMMUNODEFICIENCY VIRUS 1;

ADULT; ANTI-HIV AGENTS; CD4 LYMPHOCYTE COUNT; DISORDERS OF EXCESSIVE SOMNOLENCE; DIZZINESS; DOSE-RESPONSE RELATIONSHIP, DRUG; DOUBLE-BLIND METHOD; FEMALE; HEADACHE; HIV INFECTIONS; HIV-1; HUMANS; MALE; METABOLIC CLEARANCE RATE; MIDDLE AGED; MORPHOLINES; PLACEBOS; RECEPTORS, NEUROKININ-1; TREATMENT OUTCOME; VIRAL LOAD;

EID: 80052541730     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0024180     Document Type: Article

References (37)

1. Palella FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, et al. (1998) Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 338: 853-860.
2. Markowitz M, Nguyen BY, Gotuzzo E, Mendo F, Ratanasuwan W, et al. (2007) Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr 46: 125-133.
3. Grinsztejn B, Nguyen BY, Katlama C, Gatell JM, Lazzarin A, et al. (2007) Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet 369: 1261-1269.
4. Cahn P, Sued O, (2007) Raltegravir: a new antiretroviral class for salvage therapy. Lancet 369: 1235-1236.
5. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, et al. (2006) Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nature Medicine 12: 1365-1371.
6. Hunt PW, Brenchley J, Sinclair E, McCune JM, Roland M, et al. (2008) 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. Journal of Infectious Diseases 197: 126-133.
7. Liu Z, Cumberland WG, Hultin LE, Prince HE, Detels R, et al. (1997) Elevated CD38 antigen expression on CD8+ T cells is a stronger marker for the risk of chronic HIV disease progression to AIDS and death in the Multicenter AIDS Cohort Study than CD4+ cell count, soluble immune activation markers, or combinations of HLA-DR and CD38 expression. J Acquir Immune Defic Syndr Hum Retrovirol 16: 83-92.
8. Giorgi JV, Hultin LE, McKeating JA, Johnson TD, Owens B, et al. (1999) Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J Infect Dis 179: 859-870.
9. Deeks SG, Kitchen CM, Liu L, Guo H, Gascon R, et al. (2004) Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load. Blood 104: 942-947.
10. Ances BM, Clifford DB, (2008) HIV-associated neurocognitive disorders and the impact of combination antiretroviral therapies. Curr Neurol Neurosci Rep 8: 455-461.
11. Heaton RK, Clifford DB, Franklin DR, Woods SP, Ake C, et al. (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology 75: 2087-2096.
12. El-Sadr WM, Lundgren JD, Neaton JD, Gordin F, Abrams D, et al. (2006) CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 355: 2283-2296.
13. Danel C, Moh R, Minga A, Anzian A, Ba-Gomis O, et al. (2006) CD4-guided structured antiretroviral treatment interruption strategy in HIV-infected adults in west Africa (Trivacan ANRS 1269 trial): a randomised trial. Lancet 367: 1981-1989.
14. Severini C, Improta G, Falconieri-Erspamer G, Salvadori S, Erspamer V, (2002) The tachykinin peptide family. Pharmacol Rev 54: 285-322.
15. Marriott I, Bost K, (2001) Academic Press.
16. Douglas SD, Ho WZ, Gettes DR, Cnaan A, Zhao H, et al. (2001) Elevated substance P levels in HIV-infected men. Aids 15: 2043-2045.
17. Douglas SD, Cnaan A, Lynch KG, Benton T, Zhao H, et al. (2008) Elevated substance P levels in HIV-infected women in comparison to HIV-negative women. AIDS Res Hum Retroviruses 24: 375-378.
18. Lai JP, Ho WZ, Zhan GX, Yi Y, Collman RG, et al. (2001) Substance P antagonist (CP-96,345) inhibits HIV-1 replication in human mononuclear phagocytes. Proc Natl Acad Sci U S A 98: 3970-3975.
19. Manak MM, Moshkoff DA, Nguyen LT, Meshki J, Tebas P, et al. (2010) Anti-HIV-1 activity of the neurokinin-1 receptor antagonist aprepitant and synergistic interactions with other antiretrovirals. Aids 24: 2789-2796.
20. Wang X, Douglas SD, Song L, Wang YJ, Ho WZ, (2008) Neurokinin-1 receptor antagonist (aprepitant) suppresses HIV-1 infection of microglia/macrophages. J Neuroimmune Pharmacol 3: 257-264.
21. Campbell DE, Bruckner P, Tustin NB, Tustin R, Douglas SD, (2009) Novel method for determination of substance P levels in unextracted human plasma by using acidification. Clin Vaccine Immunol 16: 594-596.
22. Wu D, Paul DJ, Zhao X, Douglas SD, Barrett JS, (2009) A sensitive and rapid liquid chromatography-tandem mass spectrometry method for the quantification of the novel neurokinin-1 receptor antagonist aprepitant in rhesus macaque plasma, and cerebral spinal fluid, and human plasma with application in translational NeuroAIDs research. J Pharm Biomed Anal 49: 739-745.
23. Lai JP, Lai S, Tuluc F, Tansky MF, Kilpatrick LE, et al. (2008) Differences in the length of the carboxyl terminus mediate functional properties of neurokinin-1 receptor. Proc Natl Acad Sci U S A 105: 12605-12610.
24. Geracioti TD, Carpenter LL, Owens MJ, Baker DG, Ekhator NN, et al. (2006) Elevated cerebrospinal fluid substance p concentrations in posttraumatic stress disorder and major depression. Am J Psychiatry 163: 637-643.
25. Monaco-Shawver L, Schwartz L, Tuluc F, Guo CJ, Lai JP, et al. (2010) Substance P inhibits natural killer cell cytotoxicity through the neurokinin-1 receptor. J Leukoc Biol.
26. French MA, King MS, Tschampa JM, da Silva BA, Landay AL, (2009) Serum immune activation markers are persistently increased in patients with HIV infection after 6 years of antiretroviral therapy despite suppression of viral replication and reconstitution of CD4+ T cells. J Infect Dis 200: 1212-1215.
27. Hunt PW, Martin JN, Sinclair E, Bredt B, Hagos E, et al. (2003) 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 187: 1534-1543.
28. Landay A, da Silva BA, King MS, Albrecht M, Benson C, et al. (2007) Evidence of ongoing immune reconstitution in subjects with sustained viral suppression following 6 years of lopinavir-ritonavir treatment. Clin Infect Dis 44: 749-754.
29. Friis-Moller N, Sabin CA, Weber R, d'Arminio Monforte A, El-Sadr WM, et al. (2003) Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 349: 1993-2003.
30. Kuller LH, Tracy R, Belloso W, De Wit S, Drummond F, et al. (2008) Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med 5: e203.
31. Tien PC, Choi AI, Zolopa AR, Benson C, Tracy R, et al. (2010) Inflammation and mortality in HIV-infected adults: analysis of the FRAM study cohort. J Acquir Immune Defic Syndr 55: 316-322.
32. Heaton R, Franklin D, Clifford D, Woods S, Rivera Mindt M, et al. (2009) HIV-associated neurocognitive impairment remains prevalent in the era of combination ART: the CHARTER study. Montréal, Canada.
33. Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, et al. (1998) Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 281: 1640-1645.
34. Keller M, Montgomery S, Ball W, Morrison M, Snavely D, et al. (2006) Lack of efficacy of the substance p (neurokinin1 receptor) antagonist aprepitant in the treatment of major depressive disorder. Biol Psychiatry 59: 216-223.
35. Majumdar AK, Howard L, Goldberg MR, Hickey L, Constanzer M, et al. (2006) Pharmacokinetics of aprepitant after single and multiple oral doses in healthy volunteers. J Clin Pharmacol 46: 291-300.
36. (2003) Drug approval Package. EMEND (aprepitant) Capsules. Available:http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-549_Emend.cfm.
37. Sanchez RI, Wang RW, Newton DJ, Bakhtiar R, Lu P, et al. (2004) Cytochrome P450 3A4 is the major enzyme involved in the metabolism of the Substance P receptor antagonist aprepitant. Drug Metab Dispos.