Development of aprepitant, the first neurokinin‐1 receptor antagonist for the prevention of chemotherapy‐induced nausea and vomiting

Abstract

Chemotherapy can be a life-prolonging treatment for many cancer patients, but it is often associated with profound nausea and vomiting that is so distressing that patients may delay or decline treatment to avoid these side effects. EMEND (aprepitant) is the first and only neurokinin-1 (NK-1) receptor antagonist available on the market for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV). Aprepitant acts centrally at NK-1 receptors in vomiting centers within the central nervous system to block their activation by substance P released as an unwanted consequence of chemotherapy. By controlling nausea and vomiting, EMEND helps improve patients' daily living and their ability to complete multiple cycles of chemotherapy. The development of aprepitant included a novel nanoparticle formulation to optimize oral absorption and innovative chemistry to discover a prodrug form suitable for intravenous administration to improve compliance and convenience for healthcare professionals and cancer patients.

Differential effects of aprepitant, a clinically used neurokinin-1 receptor antagonist on the expression of conditioned psychostimulant versus opioid reward

“…However, aprepitant has been used in studies using both rats and mice as an effective NK1R antagonist (Ruzza et al 2014; Utsumi et al 2016; Yamamoto et al 2014). In addition, aprepitant is already in clinical use as an antiemetic in cancer patients undergoing chemotherapy (Hargreaves et al 2011; Patel and Lindley 2003). Recently, NK1R antagonism is found to decrease alcohol craving in humans (George et al 2008).…”

Building a Better Analgesic: Multifunctional Compounds that Address Injury-Induced Pathology to Enhance Analgesic Efficacy while Eliminating Unwanted Side Effects

“…Blocking SP actions at NK 1 is an effective approach against a number of emetogens, including morphine (Hargreaves et al, 2011). These antiemetic actions of NK 1 antagonists may be the result of central actions in the chemoreceptor trigger zone, indicating the importance of BBB penetration for these compounds (Bountra et al, 1993).…”

“…Neural plasticity throughout the pain axis (Abbadie et al, 1996;Malcangio et al, 2000;Vanderah et al, 2001;Szücs et al, 2004;King et al, 2005;Wan et al, 2006;Budai et al, 2007;Christie, 2008;Richebe et al, 2012), gastrointestinal (GI)/ emesis axis (Bountra et al, 1993;Hargreaves et al, 2011), and reward pathways (Maldonado et al, 1993;Powell et al, 2003) includes enhanced signaling of substance P through NK 1 receptors, resulting from chronic pain and opioids. These data Using an Opioid Agonist/NK1 Antagonist for Chronic Pain suggest that targeting multiple molecular components may translate into safer and more efficacious pain therapeutics (Woodcock et al, 2007).…”

The neurokinin-2 receptor antagonist ibodutant improves overall symptoms, abdominal pain and stool pattern in female patients in a phase II study of diarrhoea-predominant IBS

“…Tachykinin (NK) receptor antagonists are a promising class of candidate drugs that have been investigated in several clinical trials during the last decades for their possible use in therapy of a variety of different human diseases 11 12. This promise has gone largely unfulfilled, however, considering the fact that to date only a few NK1 receptor antagonists were fully developed to registration for the treatment of chemotherapy-induced emesis 13 14. The tachykinin neurokinin-2 (NK2) receptor (with neurokinin A as the preferred endogenous ligand) is widely and abundantly expressed in the gut, airways and genitourinary tract 15 16.…”