Aprepitant: Uses and Mechanism of Action

            Aprepitant is an antiemetic medication that reduces nausea and vomiting. It can be administered orally or intravenously; the intravenous formulation is called fosaprepitant, and it is metabolized into aprepitant in the body.¹ Initially approved by the Food and Drug Administration (FDA) to reduce nausea and vomiting caused by cancer chemotherapy treatment, the uses of aprepitant have recently expanded to include the treatment of postoperative nausea and vomiting.²

            Aprepitant exerts its anti-nausea effect by binding to and blocking NK-1 receptors, which are found throughout the central and peripheral nervous system. When certain stimuli like chemotherapy drugs, toxic substances, or poisons come into contact with receptors in the brain, a neurotransmitter called substance P is released. Substance P binds strongly to the NK-1 receptors, triggering the body’s nausea and vomiting response. By binding to these same receptors, aprepitant blocks substance P, making it less likely for this response to initiate.¹

            There are some drugs with antiemetic uses that operate via different mechanisms than aprepitant. Ondansetron, for instance, blocks the 5HT₃ receptor, while certain steroids, like dexamethasone, can also ease these symptoms. When combined with aprepitant, however, the effect can be greater than it would be if the medications were given alone. One study found that combining aprepitant with ondansetron and dexamethasone more than halved the rate of nausea and vomiting in cancer patients undergoing cisplatin chemotherapy compared with those who received just ondansetron and dexamethasone.³

            Interestingly, rather than only reducing the nausea and vomiting associated with cancer chemotherapy, aprepitant has been found to target tumors themselves. This effect—which has been observed in a variety of cancers, including leukemia, esophageal cancer, and gallbladder cancer—seems to occur because the NK-1 receptor and substance P signaling pathway is highly expressed in tumors.⁴

            The exact mechanism by which aprepitant kills tumors is not clear, though several possibilities have been suggested. One theory states that aprepitant promotes apoptosis, or programmed cell death, possibly through a mechanism that involves the caspase family of proteins, which are known to be involved in apoptosis.⁵ Another paper suggests that aprepitant activates the stress response pathway in tumors, which in turn leads to necrosis, an inflammation-based form of cell death that involves various factors signaling the innate immune system to attack cells—tumors, in this case.⁶

            Another possible off-label use for aprepitant is chronic refractory pruritus, also known as chronic itch. Defined as itching that lasts more than 6 weeks, the condition can severely impact quality of life and can stem from a variety of causes. A number of studies have shown that aprepitant can reduce itching across a range of pruritus cases.⁷ Because substance P plays a major role in the onset of pruritus, aprepitant’s inhibition of this neuropeptide seems to be the mechanism responsible for this effect.⁷ One of the causes of pruritus can be cancer immunotherapy. A clinical trial set to begin enrolling patients soon will investigate using aprepitant to treat pruritus in patients receiving these therapies.⁸

            Though aprepitant has clear uses as an antiemetic medication, it has also been demonstrated to play a role in targeting tumors and in the treatment of pruritus. Further research will be needed to refine aprepitant’s uses and illuminate the mechanisms by which it achieves its desired effects.

References

1. Navari, R. M. Fosaprepitant: a neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting. Expert Rev. Anticancer Ther. 8, 1733–1742 (2008), DOI: 10.1586/14737140.8.11.1733
2. Ritchie, M. K., Patel, P. & Kohli, A. Aprepitant. in StatPearls (StatPearls Publishing, Treasure Island (FL), 2025).
3. Gralla, R. J. et al. Antiemetic efficacy of the neurokinin-1 antagonist, aprepitant, plus a 5HT3 antagonist and a corticosteroid in patients receiving anthracyclines or cyclophosphamide in addition to high-dose cisplatin. Cancer 104, 864–868 (2005), DOI: 10.1002/cncr.21222
4. Cao, X. et al. Aprepitant inhibits the development and metastasis of gallbladder cancer via ROS and MAPK activation. BMC Cancer 23, 471 (2023), DOI: 10.1186/s12885-023-10954-8
5. Javid, H., Afshari, A. R., Zahedi Avval, F., Asadi, J. & Hashemy, S. I. Aprepitant Promotes Caspase-Dependent Apoptotic Cell Death and G2/M Arrest through PI3K/Akt/NF-κB Axis in Cancer Stem-Like Esophageal Squamous Cell Carcinoma Spheres. BioMed Res. Int. 2021, 8808214 (2021), DOI: 10.1155/2021/8808214
6. Dai, X., Zhu, J., Perry, S., Jiang, Q. & Shapiro, D. J. Abstract 5995: How FDA-approved drug, Aprepitant, induces immunogenic death of cancer cells. Cancer Res. 84, 5995 (2024), https://doi.org/10.1158/1538-7445.AM2024-5995
7. He, A., Alhariri, J. M., Sweren, R. J., Kwatra, M. M. & Kwatra, S. G. Aprepitant for the Treatment of Chronic Refractory Pruritus. BioMed Res. Int. 2017, 4790810 (2017).
8. Markel, G. Aprepitant in the Management of Immune Checkpoint Inhibitors Pruritus: Pilot Study in Solid Cancer Patients. https://clinicaltrials.gov/study/NCT06931119 (2025), DOI: 10.1155/2017/4790810