Aprepitant (DB00673): A Comprehensive Monograph on a First-in-Class Neurokinin-1 Receptor Antagonist

1.0 Executive Summary

Aprepitant represents a landmark achievement in supportive care, establishing a new therapeutic class as the first-in-class, selective, high-affinity neurokinin-1 (NK-1) receptor antagonist. Its development was predicated on a sophisticated understanding of the pathophysiology of emesis, specifically targeting the substance P-mediated neural pathways responsible for delayed-phase nausea and vomiting. This mechanism distinguishes it from and makes it complementary to established antiemetics like 5-hydroxytryptamine-3 (5-HT3) receptor antagonists and corticosteroids. Clinically, Aprepitant has fundamentally altered treatment paradigms for the prevention of both Chemotherapy-Induced Nausea and Vomiting (CINV) and Postoperative Nausea and Vomiting (PONV). When integrated into a triple-therapy regimen, it has demonstrated superior efficacy over standard dual-therapy, particularly in controlling the debilitating delayed symptoms of CINV associated with highly and moderately emetogenic chemotherapies.

The pharmacological profile of Aprepitant is characterized by its ability to cross the blood-brain barrier and achieve high, sustained receptor occupancy. However, its clinical application is governed by a complex pharmacokinetic profile. Aprepitant is a substrate, a moderate inhibitor, and an inducer of the cytochrome P450 3A4 (CYP3A4) enzyme system, and an inducer of CYP2C9. This multifaceted interaction profile necessitates careful management of co-administered medications, leading to specific dose adjustments (e.g., dexamethasone), contraindications (e.g., pimozide), and significant clinical warnings (e.g., warfarin, hormonal contraceptives). The drug's poor aqueous solubility has also driven significant pharmaceutical innovation, leading to the development of an oral suspension for pediatric use, an intravenous water-soluble prodrug (fosaprepitant), and ready-to-use intravenous emulsions to overcome the limitations of oral administration. This report provides a comprehensive analysis of Aprepitant, detailing its physicochemical properties, pharmacology, clinical trial evidence, safety profile, and its evolving role within the therapeutic landscape, including emerging research into novel applications and formulations.

2.0 Introduction: The Advent of NK-1 Receptor Antagonism in Emetic Control

The management of nausea and vomiting, particularly in the contexts of oncology and surgery, has long been a cornerstone of supportive medical care. Chemotherapy-Induced Nausea and Vomiting (CINV) and Postoperative Nausea and Vomiting (PONV) are not merely discomforting side effects; they represent significant clinical challenges that can profoundly impact patient quality of life, compromise nutritional status, and jeopardize adherence to life-saving treatment regimens.[1] The incidence of PONV can be as high as 80% in high-risk patient populations, while uncontrolled CINV can lead to metabolic derangements, dehydration, and psychological distress that may cause patients to refuse further cycles of chemotherapy.[3]

The introduction of 5-hydroxytryptamine-3 (5-HT3) receptor antagonists, such as ondansetron, in the early 1990s, combined with corticosteroids like dexamethasone, revolutionized the control of acute emesis—the nausea and vomiting occurring within the first 24 hours of an emetogenic stimulus.[1] This dual-therapy approach became the standard of care. However, a critical unmet need persisted: the effective management of

delayed CINV. This secondary phase, which occurs from 24 to 120 hours after chemotherapy, remained a significant clinical issue, as it was poorly controlled by 5-HT3 receptor antagonists.[1]

This therapeutic gap was rooted in a distinct pathophysiology. While acute CINV is primarily mediated by the release of serotonin from enterochromaffin cells in the gastrointestinal tract, scientific investigation revealed that delayed CINV is largely driven by a different neurotransmitter: substance P.[2] Substance P, a neuropeptide of the tachykinin family, is released in the brain in response to cytotoxic chemotherapy and exerts its potent emetogenic effects by binding to neurokinin-1 (NK-1) receptors located in key areas of the central nervous system, including the nucleus tractus solitarius, known as the brain's vomiting center.[8]

The identification of this distinct substance P/NK-1 pathway provided a novel, rational target for drug development. Aprepitant emerged as the first therapeutic agent designed to selectively and potently block this pathway.[1] As a selective, high-affinity NK-1 receptor antagonist, Aprepitant offered a mechanism of action that was complementary, not redundant, to existing antiemetics. Its development marked a paradigm shift from a mono-pathway (serotonin) to a multi-pathway approach to emetic control. The approval of Aprepitant heralded a new era in supportive care, enabling the creation of superior triple-therapy antiemetic regimens and establishing a new standard of care for preventing both acute and, crucially, delayed CINV.[4]

3.0 Physicochemical Profile and Pharmaceutical Formulations

The clinical performance and developmental trajectory of Aprepitant are intrinsically linked to its fundamental chemical and physical characteristics. A thorough understanding of these properties is essential to appreciate its pharmacological behavior and the innovations required to formulate it into effective therapeutic products.

3.1 Chemical Identity

Aprepitant is a synthetic, morpholine-based small molecule with a complex stereochemistry that is critical to its biological activity.[11] It is systematically identified by a range of standard chemical and regulatory identifiers, which are consolidated in Table 1.

• IUPAC Name: The formal chemical name for Aprepitant is 5-ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one.[14]
• Molecular Formula: The empirical formula is C23​H21​F7​N4​O3​.[9]
• Molecular Weight: The calculated molecular weight is approximately 534.43 g/mol.[9]
• CAS Number: The unique Chemical Abstracts Service registry number is 170729-80-3.[9]

3.2 Physical Properties

Aprepitant is a white to off-white crystalline solid.[15] Its most defining physical characteristic is its poor aqueous solubility. It is described as practically insoluble in water, sparingly soluble in ethanol and isopropyl acetate, and slightly soluble in acetonitrile.[15] This lipophilic nature presents a significant biopharmaceutical challenge for oral absorption and completely precludes a simple intravenous solution, a factor that has profoundly influenced its formulation development.

3.3 Pharmaceutical Formulations

The evolution of Aprepitant's dosage forms is a clear illustration of how pharmaceutical science has worked to overcome the inherent limitations of an active molecule to meet diverse clinical needs.

• Oral Capsules (Emend®): The original formulation, approved for oral administration, is available in 40 mg, 80 mg, and 125 mg strengths.[15] To overcome the poor water solubility and achieve clinically adequate oral bioavailability (approximately 60-65%), the manufacturer employed advanced formulation techniques, including particle size reduction to create a nanocrystal formulation.[9] While effective, this manufacturing process is complex and contributes to the drug's cost.[18]
• Oral Suspension (Emend® for oral suspension): To address the needs of pediatric patients and adults who have difficulty swallowing capsules, a powder for oral suspension was developed.[20] This formulation allows for weight-based dosing in children and provides an alternative for patients with dysphagia.[21]
• Intravenous Prodrug (Fosaprepitant, Emend® for injection): A major limitation of an oral antiemetic is its impracticality for patients who are actively vomiting or are designated NPO (nothing by mouth) prior to surgery.[7] This critical clinical gap drove the development of fosaprepitant, a water-soluble phosphate ester prodrug of Aprepitant.[12] Administered intravenously, fosaprepitant is rapidly and completely converted in vivo by ubiquitous phosphatases into the active Aprepitant moiety, thereby bypassing the challenges of oral absorption and ensuring 100% bioavailability.[2]
• Intravenous Emulsions (Cinvanti®, Aponvie™): Representing a further refinement in intravenous delivery, ready-to-use injectable emulsions of Aprepitant were developed.[25] These formulations eliminate the need for reconstitution that is required for the lyophilized powder form of fosaprepitant, offering greater convenience and safety in clinical settings. The IV emulsion allows for rapid administration (e.g., a 30-second IV injection for Aponvie™) and achieves therapeutic plasma concentrations associated with high receptor occupancy within minutes, making it particularly suitable for the fast-paced environment of surgical induction.[26]

The developmental pathway from a challenging oral solid to a convenient, rapid-acting IV emulsion is a compelling example of how a drug's intrinsic physicochemical properties can serve as a powerful catalyst for pharmaceutical innovation. The progression was driven by a clear need to overcome both biopharmaceutical hurdles (poor solubility) and practical clinical barriers (inability to take oral medication), demonstrating that formulation science was as critical to Aprepitant's ultimate clinical success as the discovery of the molecule itself.

Table 1: Key Physicochemical and Identification Properties of Aprepitant

Property	Value	Source(s)
IUPAC Name	5-ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one	14
Common Synonyms	Emend, MK-0869, L-754,030, Aponvie, Cinvanti	9
DrugBank ID	DB00673	9
CAS Number	170729-80-3	9
Molecular Formula	C23​H21​F7​N4​O3​	9
Molecular Weight	534.43 g/mol	9
Appearance	White to off-white crystalline solid	15
Solubility	Practically insoluble in water; Sparingly soluble in ethanol; Soluble in DMSO	15

4.0 Comprehensive Pharmacological Profile

Aprepitant's clinical utility is defined by its precise and potent interaction with the neurokinin-1 receptor and its complex pharmacokinetic behavior, which dictates its dosing, efficacy, and potential for drug-drug interactions.

4.1 Mechanism of Action

The antiemetic effect of Aprepitant is derived from its targeted antagonism of the substance P/neurokinin-1 (NK-1) receptor pathway.[11]

• Core Mechanism: Aprepitant is a selective, high-affinity, non-peptide antagonist of the human NK-1 receptor.[8] The emetic reflex is a complex process involving multiple neurotransmitter pathways. The pathophysiology of CINV, in particular, is understood through a dual-pathway model. The acute phase (0-24 hours post-chemotherapy) is primarily driven by the release of serotonin from enterochromaffin cells in the gut, which activates 5-HT3 receptors on vagal afferent nerves.[7] In contrast, the delayed phase (24-120 hours) is largely mediated by the release of the neuropeptide substance P within the central nervous system.[2]
• Targeting the Emetic Reflex: Substance P is the preferred endogenous ligand for the NK-1 receptor. These receptors are densely concentrated in key regions of the brainstem involved in the vomiting reflex, including the nucleus tractus solitarius (NTS) and the area postrema.[9] When released in response to emetogenic stimuli like cytotoxic chemotherapy, substance P binds to these NK-1 receptors, initiating a signaling cascade that culminates in the sensations of nausea and the physical act of vomiting.[8] Aprepitant functions by competitively blocking this binding event.
• Site of Action and Selectivity: A critical feature of Aprepitant is its ability to cross the blood-brain barrier, allowing it to exert its primary antiemetic effect centrally where substance P activity is highest during the delayed phase.[15] It also acts on peripheral NK-1 receptors located throughout the gastrointestinal tract, which may contribute to its efficacy by attenuating emetic signals transmitted via the vagus nerve.[10] Aprepitant's therapeutic value is enhanced by its high degree of selectivity. It possesses little to no affinity for the receptors targeted by other antiemetic classes, including serotonin (5-HT3), dopamine, and corticosteroid receptors.[11] This specificity explains why it is used as an adjunct to, rather than a replacement for, these agents, forming the mechanistic basis for modern triple-drug antiemetic therapy.

The development of Aprepitant is a prime example of successful translational medicine. A deep, mechanistic understanding of the distinct pathophysiology of delayed CINV—specifically, its reliance on the substance P/NK-1 pathway—led directly to the identification of a novel therapeutic target. Aprepitant was subsequently designed with a mechanism of action perfectly suited to block this pathway, thereby addressing a long-standing and significant unmet clinical need.

4.2 Pharmacodynamics

The pharmacodynamic properties of Aprepitant quantify its interaction with the NK-1 receptor and the resulting physiological effects.

• Receptor Binding and Potency: Aprepitant demonstrates exceptionally high potency and affinity for the human NK-1 receptor. In vitro studies have reported a dissociation constant (Kd​) as low as 19 to 86 pM and a half-maximal inhibitory concentration (IC50​) of approximately 0.09 to 0.1 nM.[14] This indicates that very low concentrations of the drug are required to effectively block the receptor.
• Central Receptor Occupancy: The clinical efficacy of a centrally acting drug like Aprepitant depends on its ability to reach its target in the brain at sufficient concentrations for a sufficient duration. Human Positron Emission Tomography (PET) studies have been instrumental in confirming this. These studies unequivocally demonstrated that orally or intravenously administered Aprepitant crosses the blood-brain barrier and achieves high (>95%) and sustained occupancy of NK-1 receptors in the brain.[9] This high level of receptor engagement is considered a prerequisite for its potent antiemetic activity.
• Synergistic Augmentation: Aprepitant does not simply add its effect to other antiemetics; it augments their activity. Animal and human studies have consistently shown that Aprepitant enhances the antiemetic effects of both 5-HT3 receptor antagonists (e.g., ondansetron) and corticosteroids (e.g., dexamethasone).[9] This synergy is the pharmacodynamic foundation for the superior clinical efficacy observed with the triple-therapy regimen (NK-1 antagonist + 5-HT3 antagonist + corticosteroid) compared to dual therapy in preventing both acute and delayed CINV.[7]

4.3 Pharmacokinetics (ADME)

The absorption, distribution, metabolism, and excretion (ADME) profile of Aprepitant is complex and has significant clinical implications, particularly concerning drug interactions.

• Absorption: Following oral administration, Aprepitant exhibits non-linear pharmacokinetics, meaning its exposure does not increase proportionally with the dose.[12] The mean absolute oral bioavailability is approximately 60% to 65%, with specific studies reporting 67% for an 80 mg dose and 59% for a 125 mg dose.[9] Peak plasma concentrations ( Tmax​) are achieved approximately 4 hours after ingestion.[12] The bioavailability is not clinically affected by food, allowing it to be taken with or without meals.[15]
• Distribution: Aprepitant is extensively distributed throughout the body. It is highly bound to plasma proteins (>95%).[12] It has a large apparent volume of distribution at steady state ( Vdss​) of approximately 70 L, which indicates significant penetration into tissues beyond the plasma compartment.[12] As confirmed by PET studies, this includes effective penetration across the blood-brain barrier to reach its central targets.[15]
• Metabolism: Aprepitant undergoes extensive hepatic metabolism, which is the primary determinant of its drug interaction profile.[9]
• Metabolic Pathways: It is metabolized predominantly by the cytochrome P450 enzyme CYP3A4, with minor contributions from CYP1A2 and CYP2C19.[9] Metabolism occurs largely via oxidation of the morpholine ring and its side chains.[15] Seven metabolites have been identified in human plasma, all of which are only weakly active.[9]
• Complex CYP450 Interactions: The most critical pharmacokinetic feature of Aprepitant is its multifaceted interaction with the CYP450 system. It acts as a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4.[11] It is also an inducer of CYP2C9.[10] This dual inhibitor/inducer role is a pharmacological "double-edged sword." As an inhibitor of CYP3A4, it can immediately increase the levels of co-administered drugs metabolized by this enzyme; this is clinically leveraged to allow for a dose reduction of dexamethasone but poses a risk with other drugs.[37] As an inducer of CYP3A4 and CYP2C9, its effects can develop over time, leading to decreased concentrations of other drugs. This time-dependent induction explains the recommendation against chronic continuous use and is the basis for its interactions with hormonal contraceptives (CYP3A4 substrates) and warfarin (a CYP2C9 substrate).[10]
• Excretion: Aprepitant is eliminated almost exclusively via metabolism; direct renal excretion of the parent drug is negligible.[15] The metabolites are subsequently excreted in both urine and feces.[9] The apparent terminal half-life of Aprepitant ranges from approximately 9 to 13 hours, which supports the once-daily dosing regimen used for CINV prevention.[10]

Table 2: Summary of Pharmacokinetic Parameters of Aprepitant

Parameter	Value	Clinical Notes/Implications	Source(s)
Bioavailability (Oral)	~60-65% (59% for 125 mg; 67% for 80 mg)	Non-linear; bioavailability decreases with increasing dose. Not affected by food.	9
Time to Peak (Tmax)	~4 hours	Consistent time to reach maximum concentration after oral dose.	12
Protein Binding	>95%	High binding limits free drug concentration but is factored into dosing.	10
Volume of Distribution (Vdss)	~70 L	Indicates extensive distribution into tissues, including the CNS.	12
Primary Metabolic Pathway	Hepatic; primarily CYP3A4 (major), CYP1A2 & CYP2C19 (minor)	Source of numerous clinically significant drug-drug interactions.	9
Terminal Half-life (t½)	~9-13 hours	Supports once-daily dosing for the 3-day CINV regimen.	15
Elimination Route	Primarily metabolic clearance; metabolites excreted in urine and feces.	No dose adjustment needed for renal impairment.	15

5.0 Clinical Efficacy in Approved Indications

The clinical value of Aprepitant has been rigorously established through a series of large, well-designed clinical trials, securing its place in international guidelines for its two primary indications: the prevention of CINV and PONV. A central theme across its clinical development is its role in prophylaxis; it is designed to be administered before an emetogenic challenge to prevent symptoms from developing, rather than to treat them once they have occurred.[17] This preemptive strategy is fundamental to its success.

5.1 Prevention of Chemotherapy-Induced Nausea and Vomiting (CINV)

Aprepitant is indicated for use in combination with other antiemetic agents for the prevention of acute and delayed nausea and vomiting associated with both highly emetogenic cancer chemotherapy (HEC) and moderately emetogenic cancer chemotherapy (MEC).[11]

5.1.1 Efficacy in Highly Emetogenic Chemotherapy (HEC)

The initial approval and validation of Aprepitant were based on two pivotal, multinational, randomized, double-blind Phase III trials involving over 1,000 patients receiving their first course of high-dose cisplatin (>70 mg/m²).[12] These studies compared the efficacy of a triple-drug regimen (oral Aprepitant 125 mg on day 1, 80 mg on days 2-3; intravenous ondansetron on day 1; and oral dexamethasone on days 1-4) against a standard-of-care regimen (placebo + ondansetron + dexamethasone).[13]

The primary efficacy endpoint was "Complete Response," stringently defined as no emetic episodes (vomiting or retching) and no use of rescue antiemetic medication during the overall 5-day (120-hour) period post-chemotherapy.[42] The results were compelling:

• Overall Phase (0-120 hours): The Aprepitant regimen demonstrated statistically significant superiority. In a pooled analysis, 72.7% of patients in the Aprepitant group achieved a complete response, compared to 52.3% in the standard therapy group.[13]
• Delayed Phase (24-120 hours): The most profound benefit was observed in the delayed phase, directly validating the drug's substance P-targeting mechanism. Complete response rates were significantly higher with Aprepitant (e.g., 75% vs. 56% in one study).[13]
• Acute Phase (0-24 hours): The Aprepitant regimen also provided superior protection in the acute phase, highlighting its ability to augment the effects of the 5-HT3 antagonist and corticosteroid.[13]

These landmark trials established the triple-therapy regimen with an NK-1 antagonist as the new standard of care for HEC.

5.1.2 Efficacy in Moderately Emetogenic Chemotherapy (MEC)

Following its success in HEC, the utility of Aprepitant was evaluated in the MEC setting, which includes common regimens such as those containing anthracyclines and cyclophosphamide (AC).[44] A large, randomized, double-blind trial compared the Aprepitant triple-therapy regimen to a standard dual-therapy regimen (ondansetron + dexamethasone) in over 800 patients receiving MEC.[13]

• Key Outcome: The study met its primary endpoint, with a significantly higher proportion of patients in the Aprepitant group achieving a complete response in the overall phase (51% vs. 42%; p=0.015).[13] This confirmed the benefit of adding an NK-1 antagonist for patients receiving MEC, particularly those at higher risk, such as patients on AC regimens.

5.1.3 Pediatric Use

The indication for CINV was later expanded to include pediatric patients aged 6 months and older. This approval was based on a pivotal study that demonstrated adding Aprepitant to a standard ondansetron-based regimen resulted in a clinically meaningful and statistically significant improvement in the control of CINV in children and adolescents receiving HEC or MEC.[47] Complete response in the delayed phase was achieved by 50.7% of patients on the Aprepitant regimen compared to only 26.0% in the control group.[13]

5.2 Prevention of Postoperative Nausea and Vomiting (PONV)

Aprepitant is also approved for the prevention of PONV in adults, administered as a single 40 mg oral dose within 3 hours prior to the induction of anesthesia.[12] PONV is a multifactorial complication, with risk predicted by the Apfel score, which considers female gender, non-smoking status, history of PONV or motion sickness, and the use of postoperative opioids.[12]

Pivotal Phase III trials for this indication were randomized, double-blind, and placebo-controlled, enrolling patients at high risk for PONV undergoing procedures such as open abdominal surgery.[5]

• Primary Endpoints: The primary measures of efficacy were typically complete response (no vomiting and no use of rescue antiemetics) during the first 24 hours and 48 hours after surgery.[50]
• Key Outcomes:
• Aprepitant 40 mg was significantly more effective than placebo in preventing vomiting and reducing the need for rescue medication over 48 hours.[5]
• In comparative studies, Aprepitant demonstrated superiority to the standard 5-HT3 antagonist ondansetron, particularly in preventing vomiting during the 24-48 hour postoperative period, a timeframe analogous to the "delayed phase" of CINV.[6] A systematic review and meta-analysis confirmed that Aprepitant significantly reduces the incidence of vomiting on both postoperative day 1 and day 2 compared to controls.[54]

The consistent efficacy of Aprepitant across these distinct clinical settings underscores the importance of the substance P/NK-1 pathway as a key mediator of emesis triggered by both cytotoxic drugs and the multifactorial stresses of surgery and anesthesia.

6.0 Safety, Tolerability, and Risk Management

While Aprepitant has demonstrated significant efficacy, its safe and effective use requires a thorough understanding of its adverse effect profile, contraindications, and, most critically, its complex potential for drug-drug interactions stemming from its metabolism.

6.1 Adverse Effect Profile

In extensive clinical trials, Aprepitant has been shown to be generally well-tolerated, with a safety profile often comparable to that of standard antiemetic therapies like ondansetron.[7] It is notably not associated with adverse effects common to other antiemetic classes, such as QT prolongation, sedation, or extrapyramidal symptoms.[39]

• Common Adverse Events: The most frequently reported adverse reactions (generally with an incidence ≥3%) in clinical studies include fatigue, asthenia (weakness), hiccups, constipation, diarrhea, headache, loss of appetite, and transient elevations in liver enzymes (ALT, AST).[20] In pediatric patients, hiccups and flushing are among the most common side effects.[46]
• Serious Adverse Events: Although rare, serious hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported during or soon after administration of intravenous or oral Aprepitant. Symptoms can include dyspnea, eye swelling, flushing, pruritus, and wheezing, requiring immediate medical attention and discontinuation of the drug.[20] Severe dermatologic reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have also been reported post-marketing.
• Black Box Warning: Aprepitant does not carry a black box warning from the U.S. Food and Drug Administration (FDA).[27]

6.2 Contraindications and Precautions

Specific patient factors and co-administered medications preclude the use of Aprepitant or necessitate special precautions.

• Absolute Contraindications:
• Hypersensitivity: Aprepitant is contraindicated in patients with a known history of a serious hypersensitivity reaction to Aprepitant or any component of the formulation.[17]
• Concurrent use with Pimozide: Co-administration with pimozide is strictly contraindicated. Aprepitant is a moderate inhibitor of CYP3A4, the enzyme responsible for pimozide metabolism. This interaction can lead to significantly elevated pimozide plasma concentrations, which can cause serious or life-threatening cardiac arrhythmias, specifically QT prolongation and Torsades de Pointes.[12] For the same reason, co-administration with other CYP3A4 substrates that have a narrow therapeutic index and are known to prolong the QT interval, such as cisapride, terfenadine, and astemizole, is also contraindicated.[37]
• Warnings and Precautions:
• Warfarin Interaction: Aprepitant is an inducer of CYP2C9, the primary enzyme that metabolizes S-warfarin. Co-administration can lead to a clinically significant decrease in the International Normalized Ratio (INR), reducing the anticoagulant effect of warfarin. It is imperative to closely monitor the INR in patients on chronic warfarin therapy during the 2-week period following administration of an Aprepitant regimen, with particular attention on days 7 to 10.[17]
• Hormonal Contraceptive Efficacy: Aprepitant's induction of CYP3A4 can increase the metabolism of hormonal contraceptives (e.g., oral pills, patches, implants), potentially reducing their efficacy. Patients of childbearing potential must be counseled to use effective alternative or back-up methods of non-hormonal contraception during treatment and for 28 days after the last dose of Aprepitant.[17]
• Hepatic Impairment: While no dose adjustment is needed for mild-to-moderate hepatic impairment, Aprepitant should be used with caution in patients with severe hepatic impairment (Child-Pugh score >9), as pharmacokinetic data in this population are limited.[12]

6.3 Clinically Significant Drug Interactions

The complex interaction of Aprepitant with the cytochrome P450 system is its most important safety consideration and the source of the majority of its clinically relevant drug interactions. As a substrate, inhibitor, and inducer of CYP3A4, and an inducer of CYP2C9, it can both affect and be affected by a wide range of medications. A summary of the most critical interactions is provided in Table 3.

• Effects of Other Drugs on Aprepitant:
• CYP3A4 Inhibitors: Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) and moderate inhibitors (e.g., diltiazem) can substantially increase Aprepitant plasma concentrations, potentially increasing the risk of adverse reactions. Co-administration should be approached with caution.[36]
• CYP3A4 Inducers: Strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John's Wort) can significantly decrease Aprepitant plasma concentrations, which may result in a loss of antiemetic efficacy.[17] Concurrent use with strong inducers should be avoided.
• Effects of Aprepitant on Other Drugs:
• CYP3A4 Substrates: As a moderate inhibitor of CYP3A4, Aprepitant can increase the plasma concentrations of many co-administered drugs. This effect is beneficial with corticosteroids; the dose of oral dexamethasone should be reduced by approximately 50% when given with the Aprepitant CINV regimen.[37] However, this interaction necessitates caution or dose adjustments for many other drugs, including certain chemotherapeutic agents (e.g., docetaxel, vinca alkaloids), benzodiazepines (e.g., midazolam, alprazolam), and immunosuppressants (e.g., cyclosporine, tacrolimus).[12]
• CYP2C9 Substrates: As an inducer of CYP2C9, Aprepitant can decrease the plasma concentrations of substrates like warfarin (as noted above) and tolbutamide.[11]

Table 3: Clinically Significant Drug Interactions with Aprepitant

Interacting Drug/Class	Mechanism of Interaction	Effect on Aprepitant	Effect on Interacting Drug	Clinical Recommendation	Source(s)
Pimozide, Cisapride, Astemizole, Terfenadine	Aprepitant inhibits CYP3A4 metabolism of these drugs.	None	Significantly increased plasma levels, risk of life-threatening QT prolongation.	Contraindicated.	36
Strong CYP3A4 Inhibitors (e.g., Ketoconazole, Itraconazole)	Inhibit CYP3A4 metabolism of Aprepitant.	Increased plasma levels, potential for increased adverse events.	Varies	Use with caution; monitor for Aprepitant-related side effects.	17
Strong CYP3A4 Inducers (e.g., Rifampin, Carbamazepine)	Induce CYP3A4 metabolism of Aprepitant.	Decreased plasma levels, potential for reduced efficacy.	Varies	Avoid co-administration.	17
Corticosteroids (e.g., Dexamethasone, Methylprednisolone)	Aprepitant inhibits CYP3A4 metabolism of corticosteroids.	None	Increased plasma levels (AUC increased ~2.2-fold for dexamethasone).	Reduce corticosteroid dose (e.g., ~50% for oral dexamethasone) when co-administered.	13
Warfarin	Aprepitant induces CYP2C9 metabolism of warfarin.	None	Decreased plasma levels, leading to a clinically significant decrease in INR.	Monitor INR closely for 2 weeks (esp. days 7-10) after Aprepitant initiation.	17
Hormonal Contraceptives (Estrogen/Progestin-based)	Aprepitant induces CYP3A4 metabolism of contraceptive hormones.	None	Decreased plasma levels, potential for reduced contraceptive efficacy.	Advise patient to use an effective alternative or back-up non-hormonal contraceptive method during and for 28 days after treatment.	17
Certain Benzodiazepines (e.g., Midazolam, Alprazolam)	Aprepitant inhibits CYP3A4 metabolism of these drugs.	None	Increased plasma levels, potential for enhanced sedative effects.	Use with caution; consider dose reduction of the benzodiazepine.	25
Certain Chemotherapeutic Agents (e.g., Vinca alkaloids, Ifosfamide)	Aprepitant inhibits CYP3A4 metabolism of these drugs.	None	Increased plasma levels, potential for increased toxicity.	Use with caution; monitor for increased chemotherapy-related toxicity.	12

7.0 Therapeutic and Market Context

Since its approval, Aprepitant has not only established a new class of antiemetics but has also influenced the subsequent development of agents within that class. Its position in the market has evolved from a novel, patent-protected entity to a foundational therapy available in generic forms.

7.1 Comparative Analysis with Other NK-1 Antagonists

The success of Aprepitant spurred the development of other NK-1 receptor antagonists, each designed to improve upon the characteristics of the first-in-class agent. The primary competitors include its own prodrug, fosaprepitant, and second-generation agents like rolapitant and netupitant.

• Aprepitant vs. Fosaprepitant: Fosaprepitant is not a distinct therapeutic agent but rather an intravenous delivery system for Aprepitant. As a water-soluble prodrug, it is rapidly and completely converted to Aprepitant in vivo.[7] Its primary advantage is providing an IV option for patients who cannot take oral medications, ensuring 100% bioavailability and a more rapid achievement of peak plasma concentration ( Tmax​ ~30 minutes for fosaprepitant vs. ~4 hours for oral Aprepitant).[12] Once converted, it shares the identical half-life, metabolic pathways, and complex drug interaction profile of oral Aprepitant.[34] While bioequivalence studies have confirmed non-inferiority in adults, some evidence in pediatric populations suggests IV fosaprepitant may offer superior control of acute-phase CINV compared to the oral formulation, possibly due to its faster onset.[2]
• Aprepitant vs. Second-Generation Agents (Rolapitant and Netupitant): The development of newer NK-1 antagonists was clearly driven by a strategy to address the two main clinical limitations of Aprepitant: its multi-day dosing regimen and its significant CYP3A4-mediated drug interactions.
• Pharmacokinetic Advantages: The most significant differentiator is rolapitant. It possesses a much longer terminal half-life of approximately 180 hours, compared to 9-13 hours for Aprepitant.[34] This allows a single oral dose of rolapitant to provide sustained NK-1 receptor blockade for the entire 5-day period at risk for delayed CINV. Critically, rolapitant is a moderate inhibitor of CYP2D6 but does not significantly inhibit or induce CYP3A4.[34] This lack of interaction with CYP3A4 is a major clinical advantage, as it eliminates the need to adjust the dose of co-administered dexamethasone and simplifies treatment for patients on complex polypharmacy regimens. Netupitant also has a longer half-life than Aprepitant (~96 hours) but, like Aprepitant, it is an inhibitor of CYP3A4.[34]
• Formulation and Convenience: Netupitant is co-formulated in a fixed-dose combination with the second-generation 5-HT3 antagonist palonosetron (a product known as NEPA). This offers the convenience of targeting two distinct emetic pathways with a single oral capsule, reducing pill burden for the patient.[34]
• Efficacy: While all agents are highly effective, some comparative data suggest potential nuances. Head-to-head trials have shown that NEPA may provide better control of nausea over the overall 5-day period compared to an Aprepitant-based regimen.[45]

The evolution of the NK-1 antagonist class demonstrates a clear trajectory in drug development. After Aprepitant successfully validated the therapeutic target, subsequent agents were rationally designed not merely as "me-too" drugs but to specifically overcome the practical (multi-day dosing) and pharmacological (CYP3A4 interactions) hurdles of the original. This has resulted in a class of drugs with options tailored for greater safety, convenience, and ease of use in clinically complex patients.

7.2 Regulatory History and Global Market Presence

Aprepitant has a well-documented regulatory history, achieving approvals from major global agencies and establishing a worldwide presence.

• Regulatory Timeline:
• U.S. FDA: Merck & Co. received initial FDA approval for Emend® (Aprepitant) capsules on March 26, 2003, for the prevention of CINV associated with HEC.[9] This was followed by key label expansions: for MEC in October 2005, for PONV in June 2006, and for pediatric use in CINV in September 2015.[22] The intravenous prodrug, fosaprepitant, was approved in 2008.[9]
• European Medicines Agency (EMA): Marketing authorisation for Emend® was granted throughout the European Union on November 11, 2003.[9] The IV prodrug (Ivemend®) was authorized in January 2008.[61] An extension for pediatric use via a new powder for oral suspension formulation was recommended in October 2015.[62]
• Therapeutic Goods Administration (TGA), Australia: Aprepitant is approved in Australia for both CINV and PONV prevention under brand names including Emend® and Aprepitant Apotex.[24] It is classified under pregnancy category B1.[64] The TGA has also reviewed applications for new single-dose regimens.[24]
• Market Status and Generic Competition: Aprepitant was originally developed and exclusively marketed by Merck & Co..[9] Following the expiration of key patents in major markets between approximately 2018 and 2022, the market has opened to generic competition.[66] Generic versions of Aprepitant capsules are now available from multiple manufacturers, including Glenmark, Sandoz, and Torrent, leading to increased accessibility and price competition.[66]
• International Brand Names: Aprepitant is marketed globally under various brand names. While Emend® is the most recognized innovator brand name, others include Cinvanti® and Aponvie® (for IV emulsions in the US). In other regions, numerous generic and local brand names are available.[9]
• Canada: Emend [68]
• Australia: Emend, Aprepitant Apotex [63]
• India: Aprecap, Aprelief, Apretero, Emetant, Fixpritant [69]
• China: Emend, Ou ke ping [70]
• Japan: Emend, Aprepitant nk, Aprepitant sawai [70]

8.0 Emerging Research and Future Directions

While Aprepitant is firmly established for its antiemetic indications, ongoing research is exploring its potential in other therapeutic areas, driven by the widespread role of the substance P/NK-1 receptor system in various physiological processes. Concurrently, pharmaceutical development continues to seek novel formulations to improve its delivery and cost-effectiveness.

8.1 Off-Label Use in Pruritus

A compelling area of investigation is the use of Aprepitant for the management of chronic, refractory pruritus (itch).

• Mechanistic Rationale: The neurobiology of pruritus shares pathways with pain and emesis, with substance P and the NK-1 receptor playing a major role in transmitting itch signals from the periphery to the central nervous system.[12] By blocking NK-1 receptors, Aprepitant can theoretically interrupt this signaling cascade, providing an antipruritic effect.[73]
• Clinical Evidence: A growing body of evidence from case series and small studies suggests that Aprepitant can be effective in reducing severe, intractable itch from a variety of causes, including malignancy-associated pruritus and toxicities related to cancer immunotherapy.[12] The National Comprehensive Cancer Network (NCCN) guidelines acknowledge that Aprepitant may be considered for refractory pruritus caused by immunotherapy.[12] However, large-scale, randomized controlled trials are still needed to definitively establish its efficacy and safety for this off-label indication.[12]

8.2 Potential as an Anti-Neoplastic Agent

One of the most intriguing areas of future research is the potential repurposing of Aprepitant as a direct anti-cancer agent.

• Preclinical Evidence: The substance P/NK-1 receptor system is increasingly recognized as being involved in cancer pathophysiology, including processes like cell proliferation, angiogenesis (the formation of new blood vessels to feed tumors), and metastasis (the spread of cancer).[12] Preclinical studies have suggested that by blocking this system, Aprepitant may exhibit direct antiproliferative, antiangiogenic, and antimetastatic effects.[12]
• Future Potential: This research opens the possibility that Aprepitant could serve a dual role in oncology: providing superior antiemetic support while also potentially complementing the cytotoxic effects of major chemotherapeutic agents. If validated in clinical trials, this could represent a significant advancement in cancer treatment, enhancing therapeutic efficacy through a novel mechanism.[12]

8.3 Novel Formulations and Delivery Systems

The biopharmaceutical challenges posed by Aprepitant's poor water solubility continue to drive research into new and improved formulations. The goals of this research are to enhance bioavailability, simplify administration, and develop more cost-effective manufacturing processes.[18]

• Self-Emulsifying Drug Delivery Systems (SEDDS): Recent research has focused on developing semi-solid SEDDS. These lipid-based formulations can be filled into capsules and are designed to spontaneously form a fine oil-in-water nanoemulsion upon contact with gastrointestinal fluids. This process enhances the dissolution rate and absorption of poorly soluble drugs like Aprepitant, offering a potential cost-effective alternative to the complex nanocrystal technology used in the commercial capsules.[18]
• Liposomal Formulations: To improve parenteral delivery, research is underway to develop stable, ready-to-use liposomal compositions of Aprepitant. Liposomes are microscopic vesicles that can encapsulate drugs, potentially improving their stability and altering their pharmacokinetic profile.[19]
• Controlled-Release Oral Formulations: Patent applications have described novel multicomponent oral dosage forms that combine an immediate-release fraction for rapid onset of action with a controlled-release fraction for prolonged duration.[76] Such formulations could potentially optimize the pharmacokinetic profile to provide both fast and long-lasting antiemetic protection from a single dose, improving convenience and patient compliance.

9.0 Concluding Expert Analysis

Aprepitant holds an undeniable position as a landmark drug in the history of supportive care. Its introduction as the first-in-class NK-1 receptor antagonist was not merely an incremental advance but a transformative event, born from a sophisticated, mechanism-based approach to drug design. By targeting the substance P pathway, Aprepitant provided the missing piece of the puzzle for controlling delayed-phase CINV, a debilitating condition that had long resisted effective management with existing therapies. The establishment of the triple-therapy regimen (NK-1 antagonist, 5-HT3 antagonist, and corticosteroid) as the standard of care for highly and moderately emetogenic chemotherapy is a direct legacy of Aprepitant's success in pivotal clinical trials.

The drug's journey, however, also serves as a case study in the complexities of pharmacology and pharmaceutical development. Its established clinical efficacy is balanced by a significant limitation: a complex and multifaceted interaction with the cytochrome P450 enzyme system. Its role as a substrate, inhibitor, and inducer of CYP3A4, as well as an inducer of CYP2C9, creates a challenging drug-drug interaction profile that demands high clinical vigilance and careful patient management. This pharmacological intricacy, along with the biopharmaceutical hurdle of its poor water solubility, directly shaped the evolution of the entire NK-1 antagonist class. Subsequent agents, such as the long-acting rolapitant with its clean CYP3A4 profile, and the convenient fixed-dose combination of netupitant/palonosetron, were rationally designed to overcome the specific limitations first encountered with Aprepitant.

Despite the availability of these newer agents, Aprepitant remains a clinically important and widely used medication, now more accessible due to generic availability. Its efficacy is undisputed, and its safety profile is well-understood after two decades of clinical use. Furthermore, the story of Aprepitant is not yet complete. Emerging research into its potential for repurposing—as a non-sedating antipruritic agent for chronic itch or even as a novel adjunctive anti-cancer therapy—highlights the enduring scientific interest in the substance P/NK-1 pathway. The ultimate validation of these new roles will depend on the outcomes of rigorous, large-scale clinical investigations. In conclusion, Aprepitant's legacy is twofold: it fundamentally improved the standard of care for millions of patients facing emetogenic therapies, and it laid the scientific and clinical groundwork that continues to inspire innovation in both supportive care and beyond.

Works cited

1. Aprepitant for the prevention of nausea and vomiting associated with chemotherapy and postoperative recovery - PubMed, accessed August 1, 2025, https://pubmed.ncbi.nlm.nih.gov/24410507/
2. The clinical research study for fosaprepitant to prevent chemotherapy-induced nausea and vomiting: A review, accessed August 1, 2025, https://advances.umw.edu.pl/en/article/2023/32/6/701/
3. Efficacy and safety of Aprepitant-containing triple therapy for the prevention and treatment of chemotherapy-induced nausea and vomiting: A meta-analysis - PMC - PubMed Central, accessed August 1, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10681589/
4. Aprepitant for Chemotherapy-Induced Emesis (CAG-00248N) - Decision Memo - CMS, accessed August 1, 2025, https://www.cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=N&ncaid=133
5. Enhanced efficacy of aprepitant-based triple prophylaxis in ..., accessed August 1, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11872938/
6. Aprepitant in combination with palonosetron for the prevention of postoperative nausea and vomiting in female patients using intravenous patient-controlled analgesia - PubMed Central, accessed August 1, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6283706/
7. Fosaprepitant and aprepitant: an update of the evidence for their place in the prevention of chemotherapy-induced nausea and vomiting, accessed August 1, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2963924/
8. What is the mechanism of Aprepitant? - Patsnap Synapse, accessed August 1, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-aprepitant
9. Aprepitant - Wikipedia, accessed August 1, 2025, https://en.wikipedia.org/wiki/Aprepitant
10. Aprepitant - WikiAnesthesia, accessed August 1, 2025, https://wikianesthesia.org/wiki/Aprepitant
11. Aprepitant | C23H21F7N4O3 | CID 135413536 - PubChem, accessed August 1, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Aprepitant
12. Aprepitant - StatPearls - NCBI Bookshelf, accessed August 1, 2025, https://www.ncbi.nlm.nih.gov/books/NBK551588/
13. Aprepitant and Fosaprepitant: A 10-Year Review of Efficacy and ..., accessed August 1, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4391760/
14. Aprepitant, hNK1 antagonist (CAS 170729-80-3) (ab269815) - Abcam, accessed August 1, 2025, https://www.abcam.com/en-us/products/biochemicals/aprepitant-hnk1-antagonist-ab269815
15. EMEND® - accessdata.fda.gov, accessed August 1, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021549s009lbl.pdf
16. Aprepitant | CAS# 170729-80-3 | Substance P Antagonist | MedKoo Biosciences, accessed August 1, 2025, https://www.medkoo.com/products/4474
17. Aprepitant: Package Insert / Prescribing Information - Drugs.com, accessed August 1, 2025, https://www.drugs.com/pro/aprepitant.html
18. A Novel Semi-Solid Self-Emulsifying Formulation of Aprepitant for Oral Delivery: An In Vitro Evaluation - PubMed Central, accessed August 1, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10222508/
19. WO2019005830A1 - Nanosome formulations of aprepitant and methods and applications thereof - Google Patents, accessed August 1, 2025, https://patents.google.com/patent/WO2019005830A1/en
20. Aprepitant: MedlinePlus Drug Information, accessed August 1, 2025, https://medlineplus.gov/druginfo/meds/a604003.html
21. Aprepitant (oral route) - Side effects & dosage - Mayo Clinic, accessed August 1, 2025, https://www.mayoclinic.org/drugs-supplements/aprepitant-oral-route/description/drg-20066897
22. Emend (aprepitant) Capsule and Oral Suspension Pediatric Postmarketing Pharmacovigilance Review | FDA, accessed August 1, 2025, https://www.fda.gov/files/advisory%20committees/published/Emend-%28aprepitant%29-Capsule-and-Oral-Suspension-Pediatric-Postmarketing-Pharmacovigilance-Review.pdf
23. Fosaprepitant and aprepitant: an update of the evidence for their place in the prevention of chemotherapy-induced nausea and vomiting - Dove Medical Press, accessed August 1, 2025, https://www.dovepress.com/fosaprepitant-and-aprepitant-an-update-of-the-evidence-for-their-place-peer-reviewed-fulltext-article-CE
24. Australian Public Assessment Report for Aprepitant - Therapeutic Goods Administration (TGA), accessed August 1, 2025, https://www.tga.gov.au/sites/default/files/auspar-aprepitant-121112.pdf
25. Aprepitant: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed August 1, 2025, https://go.drugbank.com/drugs/DB00673
26. Clinical, Administration, and Pricing Overview (aprepitant) injectable emulsion, accessed August 1, 2025, https://formulary.aponvie.com/media/content/pdf/PONV-Formulary-Presentation.pdf
27. Aprepitant (intravenous route) - Side effects & uses - Mayo Clinic, accessed August 1, 2025, https://www.mayoclinic.org/drugs-supplements/aprepitant-intravenous-route/description/drg-20406614
28. Aprepitant | CAS 170729-80-3 | SCBT - Santa Cruz Biotechnology, accessed August 1, 2025, https://www.scbt.com/p/aprepitant-170729-80-3
29. Aprepitant | NK1 Receptor Antagonists - R&D Systems, accessed August 1, 2025, https://www.rndsystems.com/products/aprepitant_6486
30. Aprepitant | NK-1 antagonist - Focus Biomolecules, accessed August 1, 2025, https://focusbiomolecules.com/aprepitant-nk-1-antagonist/
31. go.drugbank.com, accessed August 1, 2025, https://go.drugbank.com/drugs/DB00673#:~:text=Aprepitant%20is%20a%20selective%20high,and%20vomiting%20(CI%20NV).
32. EMEND® - accessdata.fda.gov, accessed August 1, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021549s016lbl.pdf
33. Aprepitant | 99.91%(HPLC) | In Stock | Neurokinin Receptor antagonist - Selleck Chemicals, accessed August 1, 2025, https://www.selleckchem.com/products/Aprepitant.html
34. Differential pharmacology and clinical utility of rolapitant in ..., accessed August 1, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5327850/
35. Pharmacokinetics of aprepitant after single and multiple oral doses in healthy volunteers - PubMed, accessed August 1, 2025, https://pubmed.ncbi.nlm.nih.gov/16490805/
36. Indication and ISI for CINVANTI® (aprepitant) injectable emulsion - Heron Connect®, accessed August 1, 2025, https://www.heronconnect.com/CINVANTI/ISI
37. EMEND, INN-aprepitant - European Medicines Agency, accessed August 1, 2025, https://www.ema.europa.eu/en/documents/product-information/emend-epar-product-information_en.pdf
38. PHARMACOKINETICS OF APREPITANT, DEXAMETHASONE AND THEIR INTERACTION IN PATIENTS WITH CHEMOTHERAPY INDUCED NAUSEA AND VOMITING - Onderzoek met mensen, accessed August 1, 2025, https://onderzoekmetmensen.nl/en/node/52052/pdf
39. Safety Profile - APONVIE, accessed August 1, 2025, https://aponvie.com/safety/
40. This label may not be the latest approved by FDA. For current ..., accessed August 1, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/022023s021lbl.pdf
41. CENTER FOR DRUG EVALUATION AND RESEARCH - accessdata.fda.gov, accessed August 1, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/021549Orig1s010.pdf
42. Drug Criteria & Outcomes: Aprepitant (Emend) Formulary Evaluation, accessed August 1, 2025, https://www.clinician.com/articles/1622-drug-criteria-outcomes-aprepitant-emend-formulary-evaluation
43. Study Details | Aprepitant for the Prevention of Chemotherapy Induced Nausea and Vomiting (CINV) Associated With Highly Emetogenic Chemotherapy (0869-801)(COMPLETED) | ClinicalTrials.gov, accessed August 1, 2025, https://clinicaltrials.gov/study/NCT00090207
44. Aprepitant for the Prevention of Chemotherapy Induced Nausea and Vomiting (CINV)(0869-130)(COMPLETED) | ClinicalTrials.gov, accessed August 1, 2025, https://www.clinicaltrials.gov/ct2/show/NCT00337727
45. A Pragmatic Study Evaluating NEPA Versus Aprepitant for Prevention of Chemotherapy‐Induced Nausea and Vomiting in Patients Receiving Moderately Emetogenic Chemotherapy - PMC, accessed August 1, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8488783/
46. Emend | European Medicines Agency (EMA), accessed August 1, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/emend
47. FDA Approves Pediatric Indication for EMEND® (aprepitant) Capsules in Combination with Other Antiemetic Agents - Merck.com, accessed August 1, 2025, https://www.merck.com/news/fda-approves-pediatric-indication-for-emend-aprepitant-capsules-in-combination-with-other-antiemetic-agents/
48. Evaluating Aprepitant single-dose plus granisetron and dexamethasone in children receiving highly emetogenic chemotherapy for the prevention of chemotherapy-induced nausea and vomiting: A triple-blinded randomized clinical trial - PubMed Central, accessed August 1, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10499563/
49. Study to Evaluate Anti-emetic Effect of Aprepitant Versus Placebo in Children and Adolescent Receiving Chemotherapy | ClinicalTrials.gov, accessed August 1, 2025, https://clinicaltrials.gov/study/NCT01402024
50. Study Details | Aprepitant for PONV Prophylaxis in Outpatient Plastic Surgery, accessed August 1, 2025, https://clinicaltrials.gov/study/NCT00659945
51. Aprepitant Completed Phase 3 Trials for Post Operative Nausea and Vomiting (PONV) Prevention - DrugBank, accessed August 1, 2025, https://go.drugbank.com/drugs/DB00673/clinical_trials?conditions=DBCOND0076946&phase=3&purpose=prevention&status=completed
52. Aprepitant for Prevention of Postoperative Nausea and Vomiting in Elective Hysterectomy, accessed August 1, 2025, https://clinicaltrials.gov/ct2/show/NCT00888329
53. Study Details | Aprepitant With Dexamethasone Versus Ondansetron With Dexamethasone for PONV Prophylaxis in Patients Having Craniotomy | ClinicalTrials.gov, accessed August 1, 2025, https://clinicaltrials.gov/study/NCT00734929
54. Aprepitant for postoperative nausea and vomiting: A systematic review and meta-analysis, accessed August 1, 2025, https://profiles.wustl.edu/en/publications/aprepitant-for-postoperative-nausea-and-vomiting-a-systematic-rev
55. FDA Updates Warning Labels of ESAs in Cancer Patients - CancerNetwork, accessed August 1, 2025, https://www.cancernetwork.com/view/fda-updates-warning-labels-esas-cancer-patients
56. CYTOCHROME P450 DRUG INTERACTION TABLE, accessed August 1, 2025, https://drug-interactions.medicine.iu.edu/Main-Table.aspx
57. Cinvanti, Emend PO (aprepitant) dosing, indications, interactions, adverse effects, and more, accessed August 1, 2025, https://reference.medscape.com/drug/cinvanti-emend-po-aprepitant-342044
58. Comparison of oral aprepitant and intravenous fosaprepitant for prevention of chemotherapy-induced nausea and vomiting in pediatric oncology patients: a randomized phase III trial, accessed August 1, 2025, https://tp.amegroups.org/article/view/120712/html
59. A systematic review and meta-analysis on evaluating the efficacy and safety of netupitant/palonosetron compared to aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients undergoing emetogenic chemotherapy. | Journal of Clinical Oncology - ASCO Publications, accessed August 1, 2025, https://ascopubs.org/doi/10.1200/JCO.2025.43.4_suppl.823
60. Drug Approval Package: EMEND (Aprepitant) NDA #21-549 - accessdata.fda.gov, accessed August 1, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-549_Emend.cfm
61. Ivemend | European Medicines Agency (EMA), accessed August 1, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/ivemend
62. EMA Adopts a Positive Opinion Recommending Changes to the Terms of the Marketing Authorisation for Aprepitant - ESMO, accessed August 1, 2025, https://www.esmo.org/oncology-news/archive/ema-adopts-a-positive-opinion-recommending-changes-to-the-terms-of-the-marketing-authorisation-for-aprepitant
63. Aprepitant (Apotex) - Healthdirect, accessed August 1, 2025, https://www.healthdirect.gov.au/medicines/brand/amt,1385201000168106/aprepitant-apotex
64. Aprepitant Use During Pregnancy - Drugs.com, accessed August 1, 2025, https://www.drugs.com/pregnancy/aprepitant.html
65. Aprepitant - Drug Targets, Indications, Patents - Patsnap Synapse, accessed August 1, 2025, https://synapse.patsnap.com/drug/b7dfb347194c4d72810c5a6e6d2afe99
66. Generic APREPITANT INN equivalents, pharmaceutical patent and freedom to operate - DrugPatentWatch, accessed August 1, 2025, https://www.drugpatentwatch.com/p/generic/aprepitant
67. Generic Emend Availability - Drugs.com, accessed August 1, 2025, https://www.drugs.com/availability/generic-emend.html
68. Emend (Aprepitant) - PharmaServe Canada, accessed August 1, 2025, https://pharmaserve.com/pharmacy_drugs/emend-aprepitant/
69. Aprepitant Capsules - Aark Pharmaceuticals, accessed August 1, 2025, https://aarkpharma.com/aprepitant/
70. Aprepitant | Drug Lookup | Pediatric Care Online - AAP Publications, accessed August 1, 2025, https://publications.aap.org/pediatriccare/drug-monograph/18/6016/Aprepitant
71. Aprecap 125mg/80mg (Aprepitant) Capsule - Amari Trade Alliance LLP, accessed August 1, 2025, https://www.amariindia.com/products/aprecap-125mg80mg-aprepitant-capsule/
72. Comparison of Pharmacokinetics of Aprepitant in Healthy Chinese and Caucasian Subjects - PMC - PubMed Central, accessed August 1, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7102878/
73. Aprepitant: Uses and Mechanism of Action - DFW Anesthesia Professionals, accessed August 1, 2025, https://anesthesiologydfw.com/aprepitant-uses-and-mechanism-of-action/
74. Vol. 2 No. 15 Aprepitant (Emend®) for Refractory Nausea - TODAY'S TOPIC:, accessed August 1, 2025, https://dam.upmc.com/-/media/upmc/services/palliative-and-supportive-institute/for-professionals-and-students/the-tablet/2022/the-tablet-v2n15-aprepitant-for-refractory-nausea.pdf?la=en&rev=6f8caf1972da430f937bac88de3dc0b7&hash=A50F5FFA99FC551F2BCE22349FAA4A48
75. A Novel Semi-Solid Self-Emulsifying Formulation of Aprepitant for Oral Delivery: An In Vitro Evaluation - PubMed, accessed August 1, 2025, https://pubmed.ncbi.nlm.nih.gov/37242751/
76. WO2018115888A1 - Novel formulations of aprepitant - Google Patents, accessed August 1, 2025, https://patents.google.com/patent/WO2018115888A1/en