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Aprepitant

Aprepitant is a selective antagonist of the neurokinin 1 (NK₁) receptor, a medication primarily used to prevent acute and delayed nausea and vomiting induced by highly or moderately emetogenic chemotherapy.^[1] It functions by blocking the action of substance P, a neuropeptide involved in the emetic reflex, in the central nervous system and gastrointestinal tract, thereby inhibiting emesis signals.^[2] Chemically, aprepitant is a white to off-white crystalline solid with the molecular formula C₂₃H₂₁F₇N₄O₃ and a molecular weight of 534.43, making it practically insoluble in water but sparingly soluble in ethanol and isopropyl acetate.^[3] Developed as an antiemetic agent, aprepitant was first approved by the U.S. Food and Drug Administration (FDA) in 2003 under the brand name Emend for the prevention of chemotherapy-induced nausea and vomiting (CINV); an indication for postoperative nausea and vomiting (PONV) was approved in 2006 but removed from the label in 2019.^[2]^[4] Pediatric indications for patients 12 years and older were approved in 2015.^[5] It is typically administered orally in capsule form (40 mg, 80 mg, or 125 mg) as part of a multidrug regimen that includes a 5-HT₃ receptor antagonist (such as ondansetron) and a corticosteroid (such as dexamethasone); for CINV, the standard regimen involves a 125 mg dose one hour before chemotherapy on day 1, followed by 80 mg once daily on days 2 and 3.^[1] An intravenous prodrug, fosaprepitant, was approved in 2008 and converts to aprepitant in the body, offering an alternative for patients unable to take oral medications.^[2] Off-label uses include the management of chronic refractory pruritus and potentially other conditions involving substance P pathways, though evidence for these applications remains limited.^[1] Aprepitant exhibits favorable pharmacokinetics, with high bioavailability (approximately 60-65%) after oral administration, extensive protein binding (over 95%), and a half-life of about 9-13 hours, allowing once-daily dosing.^[1] As a substrate, moderate inhibitor, and inducer of the cytochrome P450 3A4 (CYP3A4) enzyme, it can interact with numerous drugs metabolized by this pathway, including warfarin, oral contraceptives, and certain chemotherapeutics, necessitating dose adjustments or monitoring.^[3] Common adverse effects include fatigue, diarrhea, constipation, hiccups, and headache, occurring in more than 10% of patients, while serious risks such as hypersensitivity reactions or hepatotoxicity are rare, with transient mild elevations in liver enzymes noted in about 6% of users but rarely leading to clinical injury.^[1]^[2] Contraindications include hypersensitivity to the drug and concurrent use with pimozide, cisapride, terfenadine, or astemizole due to risk of QT prolongation and serious arrhythmias.^[3] Overall, aprepitant has significantly improved the control of CINV, reducing the incidence of these debilitating side effects in cancer patients and enhancing quality of life during treatment.^[6]

Medical Uses

Indications

Aprepitant is primarily indicated, in combination with other antiemetic agents such as dexamethasone and a 5-HT₃ receptor antagonist, for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC), including high-dose cisplatin, in adults and pediatric patients aged 6 months and older.^[4] It is also indicated for the prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC) in adults and pediatric patients aged 6 months and older.^[4] For CINV prevention, the regimen typically involves an initial 125 mg dose orally or intravenously on day 1, approximately 1 hour prior to chemotherapy, followed by 80 mg once daily on days 2 and 3.^[7] As a secondary indication, aprepitant is approved for the prevention of postoperative nausea and vomiting (PONV) in adults, administered as a single 40 mg oral dose within 3 hours prior to induction of anesthesia.^[4] This use leverages aprepitant's action as a neurokinin 1 (NK₁) receptor antagonist to complement existing antiemetic therapies in the perioperative setting.^[8] Historically, aprepitant has been explored in off-label contexts, such as for radiation-induced nausea, though these applications remain unapproved and without established clinical guidelines.

Administration and Dosage

Aprepitant is available as oral capsules in 40 mg, 80 mg, and 125 mg strengths, as well as an oral suspension at a concentration of 25 mg/mL for pediatric patients who cannot swallow capsules.^[9] The prodrug fosaprepitant is formulated as a 150 mg lyophilized powder for intravenous reconstitution and infusion.^[7] Oral formulations may be administered with or without food, while fosaprepitant is infused over 20 to 30 minutes via a central or peripheral venous catheter, beginning 30 minutes before chemotherapy on day 1.^[9]^[7] For the prevention of chemotherapy-induced nausea and vomiting (CINV) in adults, the recommended oral regimen is 125 mg on day 1 approximately 1 hour prior to chemotherapy initiation, followed by 80 mg once daily on days 2 and 3 in the morning or 1 hour prior to chemotherapy if administered that day.^[9] An equivalent intravenous option is 150 mg fosaprepitant on day 1, 30 minutes before chemotherapy, followed by 80 mg oral aprepitant on days 2 and 3.^[7] In pediatric patients aged 6 months to 12 years weighing at least 6 kg, the oral dose is 3 mg/kg (maximum 125 mg) on day 1 and 2 mg/kg (maximum 80 mg) on days 2 and 3, administered 1 hour prior to chemotherapy or in the morning on subsequent days.^[9] For pediatric intravenous dosing, fosaprepitant is given as 4 mg/kg (maximum 150 mg) up to age 11 years or 150 mg for ages 12 to 17 years on day 1 for single-day regimens, with weight-based adjustments for multi-day protocols.^[7] For the prevention of postoperative nausea and vomiting (PONV) in adults, a single 40 mg oral capsule is administered within 3 hours prior to induction of anesthesia; this indication is not approved for pediatric use.^[10] No dosage adjustment is required for mild to moderate hepatic impairment or for any degree of renal impairment, though patients with severe hepatic impairment should be monitored closely due to limited data.^[9]^[7] The CINV regimen is limited to 3 days of treatment, while PONV requires only a single dose.^[9]^[10]

Adverse Effects

Aprepitant is generally well-tolerated, with most adverse effects being mild to moderate in severity. Common side effects occurring in more than 3% of patients during clinical trials for the prevention of chemotherapy-induced nausea and vomiting (CINV) include fatigue, diarrhea, constipation, hiccups, and asthenia. In pooled trials involving highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC), these effects were reported at the following incidences in patients receiving the aprepitant regimen compared to standard therapy (as of 2022 label):

Adverse Effect	Incidence in Aprepitant Group (%)	Incidence in Standard Therapy Group (%)
Fatigue	13	12.2
Diarrhea	8.6	7.9
Hiccups	5.0	3.0

Constipation occurred at similar rates between groups. Adverse events in MEC trials were generally similar to those in HEC trials.^[9] Serious adverse effects are rare but include hypersensitivity reactions such as anaphylaxis, flushing, and dyspnea, which have been reported primarily with the intravenous formulation (fosaprepitant or IV aprepitant) at an incidence of less than 0.5% based on post-marketing surveillance. These reactions typically occur during or shortly after infusion and require immediate discontinuation and supportive care. Additionally, aprepitant exposure is increased by 10-18% in patients with moderate hepatic impairment (Child-Pugh score 7-9), though no dosage adjustment is required; caution is advised due to limited data in severe impairment.^[7]^[9] No evidence of cumulative toxicity has been observed with short courses of aprepitant, which are typically administered over 3 days. Infusion-site reactions are specific to the fosaprepitant formulation, with phlebitis, erythema, and pain reported in 2-3% of cases in HEC and MEC trials, often associated with peripheral venous access and vesicant chemotherapies.^[7] Monitoring recommendations include liver function tests in patients with hepatic impairment to detect any elevations in transaminases, which occurred in 3% of patients. Severe allergic reactions should be reported immediately, with preparedness for anaphylaxis management. In postoperative nausea and vomiting (PONV) pivotal trials, the discontinuation rate due to adverse events was 0.2% for the 40 mg aprepitant dose versus 0.4% for ondansetron, indicating good tolerability, though overall adverse event incidence was similar between groups (approximately 60%).^[11]^[7] Aprepitant acts as a moderate inhibitor of CYP3A4, which may increase exposure to co-administered drugs and potentially exacerbate their adverse effects.^[11]

Pharmacology

Mechanism of Action

Aprepitant acts primarily as a selective antagonist of the neurokinin 1 (NK₁) receptor, a G-protein-coupled receptor found in the central nervous system, where it blocks the binding of substance P, the endogenous ligand for this receptor. This antagonism occurs predominantly in the emetic center located in the medulla oblongata, preventing the transmission of emetic signals.^[12] Substance P serves as a key mediator in the delayed phase of chemotherapy-induced emesis, released in response to cytotoxic agents such as cisplatin, which then binds to NK₁ receptors and activates the vomiting reflex via central pathways. By crossing the blood-brain barrier, aprepitant inhibits this substance P-mediated signaling, thereby suppressing both acute and delayed emetic responses. This mechanism complements the actions of 5-HT₃ receptor antagonists and corticosteroids, which primarily target serotonin-mediated acute emesis, providing broader coverage for emesis control.^[13]^[14] Aprepitant exhibits high potency at the human NK₁ receptor with an IC₅₀ of approximately 0.1 nM and demonstrates minimal affinity for NK₂ or NK₃ receptors, as well as other emetic-related receptors such as 5-HT₃ and dopamine receptors. Its tight binding to NK₁ receptors, facilitated by a long half-life, results in sustained receptor occupancy of over 90% for 24–48 hours following a single dose, enabling prolonged blockade of the emetic pathway.^[15]^[16]

Pharmacokinetics

Aprepitant exhibits nonlinear pharmacokinetics over the clinical dose range, with absolute oral bioavailability of approximately 60-65% for doses of 80-125 mg.^[9] The oral formulation utilizes nanocrystalline aprepitant to enhance solubility due to the drug's poor aqueous solubility.^[9] Following oral administration, peak plasma concentrations (C_max) are reached at approximately 4 hours (T_max).^[9] Intravenous fosaprepitant, a water-soluble prodrug, is rapidly and completely converted to aprepitant post-infusion, achieving 100% bioavailability and higher initial plasma concentrations compared to oral administration.^[17] Aprepitant is highly bound to plasma proteins (>95%) and has an apparent volume of distribution at steady state of approximately 70 L, indicating extensive tissue distribution.^[9] It crosses the blood-brain barrier in humans, which is consistent with its central mechanism of action.^[9] Metabolism occurs extensively in the liver, primarily via cytochrome P450 3A4 (CYP3A4), with minor contributions from CYP1A2 and CYP2C19.^[9] The main metabolic pathways involve oxidation of the morpholine ring and side chains, yielding seven identified metabolites that exhibit only weak activity relative to the parent compound; aprepitant accounts for about 24% of plasma radioactivity after dosing.^[9] Elimination is predominantly through hepatic metabolism, with less than 5% of the dose excreted unchanged in urine and the remainder as metabolites, approximately 57% in urine and 45% in feces based on radiolabeled studies.^[18] The apparent terminal half-life ranges from 9 to 13 hours, and plasma clearance is 62-90 mL/min.^[9] In special populations, pharmacokinetics show minimal clinically meaningful changes. Elderly patients exhibit 21-36% higher AUC values compared to younger adults, but no dose adjustment is required.^[9] Renal impairment does not significantly alter total aprepitant exposure, with AUC decreases of 21-42% in severe cases or end-stage renal disease, primarily due to reduced protein binding rather than clearance changes.^[9] Hepatic impairment results in small variations: AUC is 11% lower in mild cases and 10% higher in moderate cases versus healthy subjects, with no adjustment needed; data for severe impairment are lacking.^[9] Sex and race/ethnicity differences (e.g., 9-74% higher AUC in females or certain ethnic groups) are not clinically significant.^[9] Administration with a high-fat meal slightly increases oral bioavailability but has no clinically meaningful effect, requiring no dosing adjustments.^[9]

Chemistry

Structure and Properties

Aprepitant has the molecular formula C₂₃H₂₁F₇N₄O₃ and a molecular weight of 534.43 g/mol. Its IUPAC name is 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholin-4-yl]methyl]-1,2,4-triazol-3-one. The chemical structure of aprepitant centers on a morpholine ring with cis-vicinal substitution at the 2- and 3-positions: the 2-position bears an acetal-linked (1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy group, while the 3-position is substituted with a 4-fluorophenyl group; the morpholine nitrogen is connected via a methylene bridge to a 1,2,4-triazol-3-one ring. This arrangement includes three stereocenters, configured as 2R and 3S on the morpholine ring and 1R on the ethoxy moiety. These structural elements, particularly the lipophilic trifluoromethyl and fluorophenyl groups, enable high binding affinity to the NK₁ receptor. Aprepitant appears as a white to off-white crystalline powder.^[19] It exhibits poor water solubility, approximately 0.003–0.007 mg/mL across physiological pH ranges, but is highly lipophilic with a log P value of about 4.8.^[20] The compound has a melting point of 253–255 °C.^[20] Under normal storage conditions, aprepitant remains stable as a non-hygroscopic solid.^[19] To address its solubility limitations, nanoparticle formulations—typically spherical particles measuring 100–200 nm—have been developed, which enhance dissolution rates and thereby improve oral absorption.^[21]

Synthesis

The original synthesis of aprepitant, developed by Merck, is a multi-step process that begins with the condensation of N-benzyl ethanolamine with glyoxylic acid to form a key oxazinone intermediate.^[22] This intermediate undergoes stereoselective reduction, followed by coupling with (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethanol and a fluorophenyl moiety to construct the core structure, ultimately appending the triazolinone side chain.^[22] The route achieves an overall yield of approximately 20-30%, limited by multiple purifications and stereochemical control steps.^[23] An improved, greener synthetic route was later developed by Merck to address environmental concerns, employing asymmetric synthesis to establish the required stereocenters.^[23] This approach utilizes Sharpless asymmetric epoxidation to prepare the chiral (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethanol fragment, followed by ring closure to form the cis-morpholine core, reducing the number of steps to 8-10 while avoiding heavy metal reagents and achieving an overall yield exceeding 40%.^[23] The process emphasizes atom economy through convergent assembly of four complex fragments, significantly lowering waste generation to about 20% of the original route's raw material and water usage.^[23] Key challenges in aprepitant synthesis include precise control of the three stereocenters, particularly the cis configuration in the morpholine ring, and management of the reactive mixed acetal intermediate.^[22] Stereoselectivity is often achieved through crystallization-induced asymmetric transformation or chiral reduction, with L-Selectride employed for the low-temperature (-78°C) reduction of the morpholinone to the lactol intermediate in tetrahydrofuran.^[22] The prodrug fosaprepitant is synthesized by direct phosphorylation of the hydroxyl group on aprepitant's triazolone moiety using a phosphate ester reagent, such as tetrabenzyl pyrophosphate, followed by deprotection to yield the dimeglumine salt.^[24] This one-step modification enhances water solubility for intravenous administration.^[24]

Development and History

Discovery and Preclinical Development

Aprepitant was identified in the early 1990s by Merck & Co. as part of a research program aimed at developing neurokinin-1 (NK1) receptor antagonists targeting substance P to address emesis, building on efforts that began in the 1980s to explore the role of substance P in disease.^[25]^[26] The program focused on discovering small-molecule substance P antagonists (SPAs) with brain penetration to block NK1 receptors in the central nervous system, where substance P mediates emetic responses.^[25] Preclinical studies established the rationale for NK1 antagonism in preventing chemotherapy-induced emesis, demonstrating that blockade of substance P signaling effectively inhibits vomiting triggered by agents like cisplatin. In ferret models, oral administration of aprepitant (1 mg/kg) significantly reduced acute and delayed emetic episodes induced by cisplatin (8 mg/kg intraperitoneally), with over 370 emetic events observed in controls across 72 hours being largely antagonized.^[27] Similar efficacy was observed in dog models, where NK1 antagonists like aprepitant prevented cisplatin-induced vomiting, highlighting the compound's high potency, selectivity, and ability to cross the blood-brain barrier, which led to its selection over earlier leads.^[25]^[28] Key milestones in lead optimization occurred between 1993 and 1997, when Merck conducted structure-activity relationship (SAR) studies using templates from Pfizer's CP-99,994 and related analogs to refine potency and pharmacokinetics.^[25] Aprepitant emerged as the optimized candidate due to its superior profile, but its initial oral bioavailability was low (<10%) owing to poor aqueous solubility and dissolution in the gastrointestinal tract.^[25] To address this, Merck developed a novel nanocrystalline nanoparticle formulation that enhanced absorption and bioavailability, enabling effective oral dosing for further advancement.^[25] The compound, a morpholine-based NK1 antagonist, was protected by US Patent 5,719,147, filed in 1995 and issued in 1998, covering its use in therapies including emesis prevention.^[29]^[19]

Clinical Trials and Approvals

The pivotal clinical development of aprepitant focused on its role in preventing chemotherapy-induced nausea and vomiting (CINV), with two multicenter, randomized, double-blind Phase III trials evaluating the addition of aprepitant to standard antiemetic therapy (ondansetron and dexamethasone) in patients receiving cisplatin-based highly emetogenic chemotherapy. In the trial by Hesketh et al., involving 521 patients, the aprepitant regimen achieved a complete response (no emesis and no rescue therapy use) in 72.7% of patients during days 1-5 post-chemotherapy, compared to 52.3% with standard therapy alone (P < 0.001). Similarly, the Poli-Bigelli et al. trial with 547 patients reported a complete response rate of 71.5% in the aprepitant group versus 51.9% in the standard therapy group over the same period (P < 0.001). These results demonstrated superior control of both acute and delayed CINV phases, leading to U.S. Food and Drug Administration (FDA) approval of aprepitant (as Emend) on March 26, 2003, for prevention of acute and delayed CINV in adults receiving highly emetogenic chemotherapy, in combination with other antiemetics.^[30]^[31]^[32] Subsequent evaluation expanded aprepitant's indications to postoperative nausea and vomiting (PONV). Two Phase III trials (PONV Studies 1 and 2) compared a single 40 mg oral dose of aprepitant to 4 mg intravenous ondansetron in adults undergoing open abdominal surgery under general anesthesia. In PONV Study 1 (807 patients), aprepitant showed non-inferiority for complete response (no vomiting and no rescue therapy) in the first 24 hours (63.8% vs. 55.0%) and superiority for no emesis over 48 hours (81.5% vs. 66.3%; P < 0.001). In PONV Study 2 (851 patients), aprepitant was superior for no emesis in the first 24 hours (89.9% vs. 73.6%; P < 0.001) but did not meet superiority for complete response (44.8% vs. 42.3%; P = 0.61). Across both studies, aprepitant reduced the incidence of nausea and delayed the time to first vomiting episode compared to ondansetron. These findings supported FDA approval for PONV prevention in adults on June 30, 2006.^[33]^[34] Internationally, the European Medicines Agency (EMA) granted marketing authorization for aprepitant (as Emend) on November 11, 2003, for CINV prevention in adults, aligning with the FDA indication. Pediatric extensions followed, with FDA approval on September 2, 2015, for patients aged 12 years and older for CINV, and on December 21, 2015, for oral suspension in children under 12 years based on pharmacokinetic bridging and safety data from adult trials. The intravenous prodrug fosaprepitant (Emend for Injection) received FDA approval on January 25, 2008, for the same CINV indications as oral aprepitant, offering a 1-hour infusion alternative with comparable efficacy demonstrated in a Phase III noninferiority trial (complete response 71.0% vs. 67.8% for oral; P < 0.001 for noninferiority). In 2023, the FDA approved fosaprepitant injection (as Focinvez) extending use to pediatric patients 6 months and older for CINV prevention, supported by population pharmacokinetic modeling confirming similar exposure to adults.^[35]^[5]^[17]^[36] Post-marketing surveillance has confirmed aprepitant's safety profile, with no major label changes required by 2025. Generic versions of oral aprepitant capsules (40 mg, 80 mg, 125 mg) were first approved by the FDA on September 24, 2012, increasing accessibility. Early investigational efforts in major depressive disorder, including a 2006 Phase II trial, showed no significant efficacy over placebo (response rates 47% vs. 43%), prompting a shift in development focus to antiemetic applications where preclinical substance P antagonism had already proven promising for CINV control.^[37]^[38]

Research Directions

Major Depressive Disorder

Early preclinical studies in the 2000s indicated that antagonism of neurokinin-1 (NK₁) receptors could modulate the stress response by inhibiting substance P signaling in the amygdala, a brain region central to emotional processing.^[39] This suggested potential antidepressant effects through central nervous system mechanisms independent of antiemetic actions.^[40] A phase II pilot study published in 2004, involving patients with major depressive disorder, reported mood improvements with aprepitant monotherapy at doses achieving NK₁ receptor occupancy, comparable to paroxetine and superior to placebo on Hamilton Depression Rating Scale (HAM-D) scores.^[41] Subsequent phase III trials in 2005-2006, including a multicenter, randomized, double-blind study (NCT00042029) with 547 participants, evaluated aprepitant at 300 mg/day versus placebo and paroxetine (an SSRI) over 6 weeks.^[42] The trial found no significant differences in HAM-D score reductions between aprepitant and placebo (p > 0.05), despite good tolerability and no major safety concerns.^[38] Similar negative results emerged from additional phase III trials, leading to the conclusion that aprepitant lacked antidepressant efficacy at tested doses. Following these negative phase III results in 2005-2006, development for major depressive disorder was discontinued by Merck around 2007.^[38] A 2014 follow-up study examined aprepitant as an adjunct to paroxetine in patients with major depressive disorder inadequately responsive to SSRI monotherapy.^[43] Over 6 weeks, the combination (aprepitant 300 mg/day plus paroxetine 20 mg/day) showed no greater improvement in depressive symptoms compared to paroxetine plus placebo, as measured by HAM-D and Montgomery-Åsberg Depression Rating Scale scores.^[43] A 2017 review of NK₁ receptor antagonists, including aprepitant, analyzed clinical data and confirmed the overall lack of efficacy for depression treatment across multiple trials.^[44] As of 2025, no ongoing clinical trials investigate aprepitant for depression, though theoretical interest persists in NK₁ antagonism for treatment-resistant cases without supporting evidence.^[45]

Cannabinoid Hyperemesis Syndrome

Cannabinoid hyperemesis syndrome (CHS) is a disorder characterized by recurrent episodes of intractable nausea, vomiting, and abdominal pain linked to prolonged cannabis use, often presenting in cyclic patterns that mimic cyclic vomiting syndrome. Standard antiemetic agents, including ondansetron, metoclopramide, and haloperidol, frequently prove ineffective in CHS due to the central role of the neurokinin 1 (NK₁) receptor pathway, which mediates substance P signaling in the emetic center of the brainstem.^[46]^[47] Emerging evidence supports the use of aprepitant, an NK₁ receptor antagonist, for rapid symptom control in refractory CHS. A 2025 case series reported two adolescents (aged 16 and 17 years) with CHS who remained unresponsive to 36–45 hours of conventional therapies, including ondansetron, metoclopramide, and capsaicin cream; both experienced vomiting cessation within 1 hour of receiving 125 mg intravenous aprepitant, with tolerance to oral fluids in 1–2 hours and discharge the following day without further antiemetics.^[48]^[49] Similarly, a 2025 case report described a 38-year-old patient with CHS whose intractable vomiting persisted despite multiple antiemetics (promethazine, ondansetron, prochlorperazine, and droperidol) and supportive care; 150 mg intravenous fosaprepitant, the water-soluble prodrug of aprepitant, resulted in complete symptom resolution, allowing discharge after prior failures of standard CHS interventions like hot showers.^[50] A 2022 systematic review of CHS management options identified aprepitant as a targeted therapy in early cases, with one report showing full relief within 24 hours when other antiemetics failed; the proposed mechanism involves aprepitant blocking cannabis-induced substance P release and NK₁ receptor activation in the central nervous system, thereby interrupting the emetic cascade. More recent data from a 2024 retrospective analysis of 58 children with cyclic vomiting syndrome or CHS reinforced this, documenting improvement in nausea and vomiting for 84% of patients treated with aprepitant (typically a 3-day course starting at 125 mg), approximating 80–100% response rates in smaller CHS-specific subsets within 24 hours.^[46]^[51] Despite these findings, aprepitant's application in CHS is off-label, lacking support from large randomized controlled trials to confirm efficacy, optimal dosing, or long-term safety. Sustained relief depends on complete cannabis cessation, as ongoing use promotes symptom recurrence, and aprepitant addresses acute episodes rather than underlying etiology. At the 2025 American Academy of Pediatrics National Conference, the adolescent case series was presented, positioning aprepitant as a novel option for pediatric CHS refractory to first-line therapies.^[52]

Other Investigational Applications

Aprepitant has shown preliminary promise as an adjunctive therapy for managing radiation-induced nausea and vomiting in patients with head and neck cancer. In a 2022 prospective phase II trial involving 43 patients with locally advanced head and neck squamous cell carcinoma undergoing chemoradiotherapy with cisplatin, the addition of aprepitant to ondansetron and dexamethasone achieved an overall emesis-free response rate of 88.4% (95% CI: 74.9–96.1), indicating effective control of delayed emesis compared to historical standard therapy rates.^[53] This application remains unapproved and requires further validation in larger trials. Research into aprepitant's role in pruritus and wound healing has focused on its NK₁ receptor blockade to mitigate substance P-mediated inflammation. A 2023 preclinical study in diabetic mouse models of non-healing ulcers demonstrated that aprepitant accelerated wound closure by promoting re-epithelialization, collagen deposition, and angiogenesis while reducing inflammatory responses, suggesting potential benefits for diabetic foot ulcers.^[54] Human investigations, including case series on refractory pruritus in chronic wounds, have reported symptom relief.^[55] Exploratory efforts have examined aprepitant for migraine prophylaxis, leveraging its modulation of substance P pathways implicated in neurogenic inflammation. A 2016 pilot study (n=14) in patients with refractory migraine treated with inpatient IV dihydroergotamine found that oral aprepitant (125 mg day 1, 80 mg days 2–3) significantly reduced nausea scores by over 50% in most participants, though it did not directly assess attack frequency reduction and no subsequent trials have advanced this to prophylaxis.^[56] Overall, these applications remain in early stages, with all evidence limited to small-scale or preclinical investigations and no Phase III data available; broader potential exists in other substance P-related conditions such as anxiety, supported by preclinical models showing reduced stress responses via NK₁ antagonism.^[41]

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Jan 28, 2008 · CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA, ... insolubility of aprepitant in water, a specification has been set for the amount of ...
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Development of aprepitant, the first neurokinin-1 receptor antagonist ...
The development of aprepitant included a novel nanoparticle formulation to optimize oral absorption and innovative chemistry to discover a prodrug form suitable ...Missing: original | Show results with:original
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Neurokinin-1 receptor antagonists for chemotherapy-induced ...
The discovery of several NK1 receptor antagonists is a big revolution to dealt this problem. ... In the early 1990s, the first small molecule brain ...
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Comparison of three preclinical models for nausea and vomiting ...
In ferrets, cisplatin (8mg/kg, i.p.) induced acute and delayed emesis (371.8±47.8 emetic events over 72h) which was antagonized by aprepitant (1mg/kg, p.o.).
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The novel NK1 receptor antagonist MK–0869 (L ... - ScienceDirect.com
In a model of acute and delayed emesis, ferrets were dosed with cisplatin (5 mg/kg i.p.) and the retching and vomiting response recorded for 72 h. Pretreatment ...
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NK1 receptor antagonist - Wikipedia
Studies showed that the inhibition constant (Ki) for NK2 receptors was >10000-fold higher and for NK3 receptors >1000-fold higher than that for NK1 receptors.
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Substituted heterocycles of the general structural formula: are tachykinin receptor antagonists useful in the treatment of inflammatory diseases, ...
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The oral neurokinin-1 antagonist aprepitant for the prevention of ...
Conclusion: Compared with standard dual therapy, addition of aprepitant was generally well tolerated and provided consistently superior protection against CINV ...Missing: NEJM | Show results with:NEJM
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For Day 1, the complete response rates were 82.8% for the aprepitant group and 68.4% for the standard therapy group (P < 0.001); for Days 2-5, the complete ...
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Jul 6, 2003 · Drug Approval Package EMEND (Aprepitant) Capsules. Company: Merck. Application No.: 21-549. Approval Date: 3/26/2003. Date created: July 06, 2003.Missing: Generic | Show results with:Generic
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PONV Study 2 failed to satisfy its primary hypothesis that aprepitant is superior to ondansetron in the prevention of PONV as measured by the proportion of ...
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May 30, 2007 · Results: Aprepitant at both doses was non-inferior to ondansetron for complete response 0-24 h after surgery (64% for aprepitant 40 mg, 63% for ...
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Emend | European Medicines Agency (EMA)
Other information about Emend Emend received a marketing authorisation valid throughout the EU on 11 November 2003.
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Sep 2, 2015 · EMEND capsules are now approved for use in combination with other antiemetic agents in patients 12 years of age and older and patients less than 12 years who ...
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A study to evaluate pharmacokinetics, safety, and tolerability of a single dose of Fosaprepitant Injection 150 mg/50 mL (3 mg/mL) for prevention of ...
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Poorly controlled nausea and vomiting (N&V) can result in significant and severe physiologic consequences, including nutritional derangements, metabolic ...
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https://pubmed.ncbi.nlm.nih.gov/28753469/
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Addition of an NK1 receptor antagonist to an SSRI did not enhance ...
Concomitant use of aprepitant + paroxetine for 6 weeks did not provide greater antidepressant benefit compared with paroxetine + placebo in patients with ...
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Dec 1, 2017 · Aprepitant may have failed in Phase III because of an inadequate understanding of the relationship between brain NK1 receptor occupancy and ...Missing: 2006 | Show results with:2006
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Jul 31, 2024 · ... a recent review indicated new potential for aprepitant ... major depressive disorder or depressive symptoms: meta‐ analysis of clinical trials.
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A Systematic Review on Cannabis Hyperemesis Syndrome and Its ...
Nov 1, 2021 · The chronic longstanding use of cannabis has been implicated in causing refractory nausea and vomiting named cannabinoid hyperemesis syndrome.Abstract · Methods · Results · Discussion
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A Comprehensive Review and Update on Cannabis Hyperemesis ...
Cannabis hyperemesis syndrome (CHS) is a gut–brain axis disorder characterized by recurring nausea and vomiting intensified by excessive cannabis consumption.2. Pathophysiology · 2.2. Endocannabinoid System... · 5. Management
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Cannabinoid Hyperemesis Syndrome in Adolescents: The Role of ...
Sep 18, 2025 · Aprepitant, a neurokinin-1 receptor antagonist, was subsequently given, and both patients experienced rapid and sustained improvement in ...
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[PDF] Cannabinoid Hyperemesis Syndrome clinical pathway
Discontinue if any skin irritation/burning. Aprepitant. 125 mg day 1, then 80 mg days 2 and 3, after that 2x/week until symptoms cease.
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Cannabinoid Hyperemesis Syndrome Treated With Fosaprepitant
We present a case where fosaprepitant was utilized for intractable nausea and vomiting when other treatment modalities failed for CHS. Keywords: antiemetics, ...
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EFFICACY AND SAFETY OF APREPITANT FOR CHILDREN WITH ...
May 19, 2024 · Background: There is growing evidence that aprepitant can be helpful for patients with cyclic vomiting syndrome (CVS) and cannabinoid ...
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P3.005: Cannabinoid Hyperemesis Syndrome in Adolescents
P3.005: Cannabinoid Hyperemesis Syndrome in Adolescents: The Role of Aprepitant as a New Treatment Option for Rapid Symptom Relief. Sunday, September 28, 2025.
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Antiemetic prophylaxis for chemoradiotherapy-induced nausea and ...
May 30, 2022 · The present study extends the combination of aprepitant, ondansetron, and dexamethasone as antiemetic prophylaxis to patients with HNSCC ...
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Potential therapeutic effect of NK1R antagonist in diabetic non ...
These data indicated that aprepitant significantly accelerated diabetic wound healing by promoting wound re-epithelialization, collagen deposition and ...
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Aprepitant for the Treatment of Chronic Refractory Pruritus - PMC
Aprepitant was first approved in the United States in March 2003 to prevent chemotherapy-induced nausea and vomiting (CINV) [1]. The drug was originally ...
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Aprepitant for the management of nausea with inpatient IV ... - PubMed
Oct 11, 2016 · This study provides Class IV evidence that for patients with medically refractory migraine receiving IV DHE, oral aprepitant reduces nausea.Missing: prophylaxis | Show results with:prophylaxis
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Development of the 2nd generation neurokinin-1 receptor ...
A wealth of preclinical evidence implicates substance P and the neurokinin-1 (NK-1) receptor as important targets in the pathogenesis of anxiety disorders ...Abstract · Introduction · Acknowledgements