The long-range goal of this proposal is to continue to evaluate the potential role of neurokinin-1 receptor (NK1R) antagonists as anti HIV-1 agents in vivo. Aprepitant is the only FDA approved substance P antagonist. We have demonstrated in our previous work that NKIR antagonists, in general and aprepitant, in particular, have significant anti HIV-1 activity in vitro possibly mediated through CCR5 down-regulation, although some of our in vitro data suggests that these compounds have some antiviral activity in CXCR4 viruses. Aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYPIA2 and CYP2C19. This metabolic pathway suggests that aprepitant will interact favorably with the protease inhibitor ritonavir (a potent inhibitor of CYP3A4), as do many ofthe current available antlretrovirals. We will examine the safety and the PK characteristics of the NKI R antagonist, aprepitant, in HIV-infected subjects with well controlled viral replication receiving ritonavir containing antiretroviral therapy. Our hypothesis is that aprepitant will be safe, tolerable and that with the concomitant administration of the protease inhibitor ritonavir, we will be able to attain the therapeutic levels necessary to achieve antiviral activity predicted by both by our in vitro studies and our pharmacokinetic and pharmacodynamic (PK/PD) modeling. We will also examine the antiviral activity of an optimized dose of aprepitant administered for two weeks as an """"""""add on"""""""" drug in patients with evidence of virologic failure on a protease inhibitor containing regimen. Further, we hypothesize that aprepitant will improve depressive symptoms, decrease anxiety and improve sleep quality in patients with HIV infection.

Public Health Relevance

We will examine the safety and PK characteristics of aprepitant in HIV-infected subjects with well controlled viral replication, receiving ritonavir containing antiretroviral therapy. We hypothesize that aprepitant will be safe, tolerable, and will demonstrate antiviral activity. We will also examine the antiviral activity of aprepitant, optimized as an add-on drug in patients with evidence of virologic failure on a protease inhibitor containing regimen. This study is a proof-of-principal of NKI R antagonists for adjuvant therapy for neuroAIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01MH090325-05
Application #
8526563
Study Section
Special Emphasis Panel (ZMH1-ERB-X)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$300,817
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Barrett, Jeffrey S; Spitsin, Sergei; Moorthy, Ganesh et al. (2016) Pharmacologic rationale for the NK1R antagonist, aprepitant as adjunctive therapy in HIV. J Transl Med 14:148
Douglas, Steven D (2016) Substance P and sickle cell disease-a marker for pain and novel therapeutic approaches. Br J Haematol 175:187-188
McGuire, Jennifer L; Gill, Alexander J; Douglas, Steven D et al. (2015) Central and peripheral markers of neurodegeneration and monocyte activation in HIV-associated neurocognitive disorders. J Neurovirol 21:439-48
Tebas, Pablo; Spitsin, Sergei; Barrett, Jeffrey S et al. (2015) Reduction of soluble CD163, substance P, programmed death 1 and inflammatory markers: phase 1B trial of aprepitant in HIV-1-infected adults. AIDS 29:931-9
McGuire, Jennifer L; Kempen, John H; Localio, Russell et al. (2015) Immune markers predictive of neuropsychiatric symptoms in HIV-infected youth. Clin Vaccine Immunol 22:27-36
Tuluc, Florin; Meshki, John; Spitsin, Sergei et al. (2014) HIV infection of macrophages is enhanced in the presence of increased expression of CD163 induced by substance P. J Leukoc Biol 96:143-50
McGuire, Jennifer L; Barrett, Jeffrey S; Vezina, Heather E et al. (2014) Adjuvant therapies for HIV-associated neurocognitive disorders. Ann Clin Transl Neurol 1:938-52
Barrett, Jeffrey S; Bajaj, Gaurav; McGuire, Jennifer et al. (2014) Modeling and simulation approach to support dosing and study design requirements for treating HIV-related neuropsychiatric disease with the NK1-R antagonist aprepitant. Curr HIV Res 12:121-31
Barrett, Jeffrey S; McGuire, Jennifer; Vezina, Heather et al. (2013) PET measurement of receptor occupancy as a tool to guide dose selection in neuropharmacology: are we asking the right questions? J Clin Psychopharmacol 33:725-8
Schwartz, Lynnae; Spitsin, Sergei V; Meshki, John et al. (2013) Substance P enhances HIV-1 infection in human fetal brain cell cultures expressing full-length neurokinin-1 receptor. J Neurovirol 19:219-27

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