Pharmacologic rationale for the NK1R antagonist, aprepitant as adjunctive therapy in HIV

Abstract

BackgroundMany HIV infected individuals with suppressed viral loads experience chronic immune activation frequently developing neurological impairment designated as HIV associated neurocognitive disorder (HAND). Adjunctive therapies may reduce HIV associated inflammation and therefore decrease the occurrence of HAND.MethodsWe have conducted in vitro, animal and clinical studies of the neurokinin 1 receptor (NK1R) antagonist aprepitant in HIV/SIV infection.ResultsAprepitant inhibits HIV infection of human macrophages ex vivo with an ED50 ~ 5 µM. When administered at 125 mg once daily for 12 months to SIV-infected rhesus macaques, aprepitant reduced viral load by approximately tenfold and produced anti-anxiolytic effects. The anti-viral and anti-anxiolytic effects occur at approximately the third month of dosing; and the effects are sustained throughout the duration of drug administration. Protein binding experiments in culture media and animal and human plasma indicate that the free fraction of aprepitant is lower than previously reported supporting usage of higher doses in vivo. The analysis of blood samples from HIV positive individuals treated for 2 weeks with aprepitant at doses up to 375 mg demonstrated reduced levels of pro-inflammatory cytokines including G-CSF, IL-6, IL-8 and TNFα. Decreased pro-inflammatory cytokines may reduce HIV comorbidities associated with chronic inflammation.ConclusionsOur results provide evidence for a unique combination of antiretroviral, anti-inflammatory and behavioral modulation properties of aprepitant in vitro and in vivo. These results provide robust support for a clinical exposure target above that recommended for chemotherapy-induced nausea and vomiting. Doses up to 375 mg once daily in HIV-infected patients still elicit sub-therapeutic exposure of aprepitant though effective plasma concentrations can be achievable by proper dose modulation.

Truncation of neurokinin-1 receptor—Negative regulation of substance P signaling

“…Indeed, under most conditions, human monocytes, NK cells, and T‐cells express NK1R‐T . SP/NK1R‐T signaling is of major importance in immune activation . These observations support our overall hypothesis that, by expressing the truncated isoform in immune cells, NK1R alternative splicing is a negative regulator of SP signaling.…”

Role of Substance P Neuropeptide in Inflammation, Wound Healing, and Tissue Homeostasis

“…In comparison to CP-96,345, NK1R antagonist aprepitant is more potent ex vivo to suppress the HIV infection of myeloid derived macrophages (69). Aprepitant treatment has also been shown to reduce viral load in SIV-infected macaques, and reduce the pro-inflammatory cytokines in HIV positive individuals, suggesting that NK1R antagonist might be use as an adjunct therapy in HIV infection (106). …”

Substance P and sickle cell disease—a marker for pain and novel therapeutic approaches

“…Reductions in plasma SP levels and pro-inflammatory cytokines, including granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-6, IL8 and TNF-α, have been demonstrated in Phase IB clinical trials of a neurokinin-1 receptor antagonist in human immunodeficiency virus (HIV) (Tebas et al 2001; Valverde et al 2016) (NIH clinicaltrials.gov; NCT00428519; NCT01300988). The clinical efficacy of neurokinin-1 receptor antagonists are contingent on receptor occupancy, protein binding and complex pharmacometric analysis, which we have recently investigated in relationship to the potential use of aprepitant, as adjunctive therapy in HIV-infected subjects (Barret et al 2016). Aprepitant (Emend) is the only US Food and Drug Administration (FDA)-licensed neurokinin-1 receptor antagonist and has been licensed for chemotherapy-induced nausea and vomiting (CINV).…”

“…Moreover, and of direct relevance, the studies of SP and Neuorkinin-1 (Michaels et al, 1998;Tebas et al, 2011Tebas et al, , 2015Douglas, 2008;Douglas & Leeman, 2011;Barrett et al, 2016;Douglas et al, 2016), and the findings of Brandow et al (2016), are the observations of elevated plasma SP in the HBSS-BERK mouse, designated as the transgenic sickle cell mouse (Vincent et al, 2013). HBSS-BERK is the sickle cell mouse with murine a and b globin knockouts that expresses human sickle or normal haemoglobin A.…”