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"Emend" redirects here. For "Emend for Injection", see Fosaprepitant.

Aprepitant (brand name: Emend (the brand name used in all English-speaking countries)) is an antiemetic chemical compound that belongs to a class of drugs called substance P antagonists (SPA). It mediates its effect by blocking the neurokinin 1 (NK₁) receptor.

Aprepitant is manufactured by Merck & Co. under the brand name Emend for prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) and for prevention of postoperative nausea and vomiting. It was approved by the FDA in 2003.^[1]

Aprepitant may also be useful in the treatment of cyclic vomiting syndrome but there are few studies to date.

On January 2008, the FDA approved fosaprepitant, an intravenous form of aprepitant, which is to be sold under the tradename Emend Injection in the US and as Ivemend in some other countries.

Initial development[edit]

Acute or delayed CINV is an unpleasant side effect experienced by over 80% of patients undergoing initial and repeated highly emetogenic cancer chemotherapy, for example cisplatin. Throughout the 1990s a noticeable increase occurred in the number of diagnosed cancer patients undergoing chemotherapy and therefore experiencing CINV. As a result of this, toward the end of the decade, initial research was conducted to try to develop a drug that eases the severity and decreases the likelihood of CINV, and after several years of research Merck & Co. successfully developed a drug known as Emend.

The active substance of Emend is aprepitant, which is effective in helping to prevent CINV because it antagonizes the NK1 receptor. This receptor is located at the brain stem nuclei of the dorsal vagal complex and is a crucial part of the regulation of vomiting. This is due to the receptor binding with substance P, a peptide neurotransmitter.

Structure and properties of aprepitant[edit]

Aprepitant is made up of a morpholine core with two substituents attached to adjacent ring carbons. These substitute groups are trifluoromethylated phenyl ethanol and fluorophenyl group. Aprepitant also has a third substituent (triazolinone), which is joined to the morpholine ring nitrogen. This means that aprepitant is made up of three chiral centres very close together, which combine to produce an amino acetal arrangement. It also means that the empirical formula of the substance is C₂₃H₂₁F₇N₄O₃.

Aprepitant is an off-white crystalline solid that has a molecular weight of around 534.53. It has a very limited solubility in water. It does have a reasonably high solubility in non-polar molecules such as oils. This would, therefore, suggest that aprepitant as a whole, despite having components that are polar, is a non-polar substance.

Synthesis[edit]

Shortly after Merck initiated research into the reducing the severity and likelihood of CINV, researchers discovered that aprepitant is effective in prevention. Researchers worked on coming up with a process to create aprepitant, and within a short period they came up with effective synthesis of the substance. This original synthesis was deemed to be workable and proved to be a crucial step in achieving commercialization; however, Merck decided that the process was not environmentally sustainable. This was due to the original synthesis requiring six steps, many of which needed dangerous chemicals such as sodium cyanide, dimethyltitanocene, and gaseous ammonia. In addition to this, for the process to be effective cryogenic temperatures were needed for some of the steps and other steps produced hazardous by products such as methane and magnesium chloride. ^[2] The environmental concerns of the synthesis of aprepitant became so great that Merck research team decided to withdraw the drug from clinical trials and attempt to create a different synthesis of aprepitant. ^[3]

The gamble of taking the drug out of clinical trials proved to be successful when shortly afterwards the team of Merck researchers came up with an alternative and more environmentally friendly synthesis of aprepitant. The new process works by four compounds of similar size and complexity being fused together. This therefore is a much simpler process and requires only three steps, half the number of the original synthesis.

The new process begins by enantiopure trifluoromethylated phenyl ethanol being joined to a racemic morpholine precursor. This results in the wanted isomer crystallizing on the top of the solution and the unwanted isomer remaining in the solution. The unwanted isomer is then converted to the wanted one by the chemist controlling the reaction conditions and a process known as crystallization-induced asymmetric transformation occurring. By the end of this step a secondary amine, the base of the drug, is formed.

The second step involves the fluorophenyl group being attached to the morpholine ring. Once this has been achieved the third and final step can initiated. This step involved a side chain of triazolinone being added to the ring. Once this step has been successfully completed a stable molecule of aprepitant has been produced. ^[4]

This more streamlined route yields around 76% more aprepitant than the original process and reduces the operating cost by a significant amount. In addition, the new process also reduces the amount of solvent and reagents required by about 80% and saving an estimated 340,000L per ton of aprepitant produced. ^[3]

As a result of the improvements in the efficiency and reduction of environmental impacts of the synthesis of aprepitant, several social benefits have occurred.^{[citation needed]} The most noticeable of which is a reduction in the price of the drug. This has resulted in a greater number of patients having access to it, which therefore has caused a decrease in the number of people that undergo chemotherapy experiencing CINV. The improvements in the synthesis process have also resulted in a decrease in the number long-term detrimental to the natural environment, due to elimination of hazardous chemicals from the procedure of this technique

Drug development[edit]

Once the effective synthesis of aprepitant was discovered, the next step taken by Merck was to develop a pharmaceutical drug that incorporates the active substance in it.

Researches began to analyse aprepitant and make observations about its chemical and physical properties. It was discovered that the substance has a low aqueous solubility. As a result of this the product development focused on reducing the size of aprepitant’s particles to a nanoscale. This therefore would increase the bioavailability of the drug.

Using this information Merck came up with a manufacturing process, (which is still used today). This nine step process includes wet milling, which reduces the particle size of the active ingredient. It also involves excipients being used to keep the nanoparticles of aprepitant separated from each other during and after the microcrystalline celluse beads being coated. This therefore prevents agglomerating of the beads, which means that nanoparticles of aprepitant remains small even after it is re dispersed from the beads.

The nine-step manufacturing process involves

A slurry of aprepitant, hydroxypropyl cellulose, and water being produced
The slurry undergoing pre-milling
An aqueous sucrose dispersion being added to the slurry
The slurry undergoing media-milling that produces a colloidal dispersion
An aqueous sucrose dispersion being added to the slurry
The microcrystalline cellulose beads being spray coated with the colloidal dispersion.
The coated beads being sieved
The coated microcrystalline cellulose beads are blended with micronised sodium lauryl sulfate
The blended beads are encapsulated

The end result of the nine step process is a capsule, known as Emend, which contain aprepitant. The capsule also contains several other substances, which includes sucrose, hydroxypropyl cellulose, microcrystalline cellulose, sodium lauryl sulfate, gelatin, shellac, black iron oxide and titanium dioxide.

Mechanism of action[edit]

Aprepitant is classified as an NK1 antagonist because it blocks signals given off by NK1 receptors. This, therefore, decreases the likelihood of vomiting in patients. Emend is usually taken as a preventative for chemotherapy-induced nausea and vomiting, which is a serious side-effect experienced by over 80% of patients who undergo chemotherapy.

NK1 is a G protein-coupled receptor and is located in the central nervous system and the peripheral nervous system. This receptor has a dominant ligand known as Substance P (SP). SP is a neuropeptide, composed of 11 amino acids, which sends and receives impulses and messages from the brain. It is found in high concentrations in the vomiting center of the brain, and, when activated, it results in a vomiting reflux occurring. In addition to this it also plays a key part in the transmission of pain impulses from the peripheral receptors to the central nervous system.

Aprepitant has been shown to inhibit both the acute and delayed emesis induced by cytotoxic chemotherapeutic drugs by blocking substance P landing on receptors in the brain's neurons. This has been proven by Positron Emission Tomography (PET) studies, which have demonstrated that aprepitant can penetrate the brain and NK1 receptors in the brain. ^[5] It has also been shown to increase the activity of the 5-HT3 receptor antagonists ondansetron and the corticosteroid dexamethasone, which are also used to prevent nausea and vomiting caused by chemotherapy.^[6]

Aprepitant is taken orally in the form of a capsule. Before clinical testing, a new class of therapeutic agent has to be characterized in terms of preclinical metabolism and excretion studies. Average bioavailability is found to be around 60-65%. Aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. Seven metabolites of aprepitant, which are only weakly active, have been identified in human plasma. As a moderate inhibitor of CYP3A4, aprepitant can increase plasma concentrations of co-administered medicinal products that are metabolized through CYP3A4. Specific interaction has been demonstrated with oxycodone, where aprepitant both increased the efficacy and worsened the side effects of oxycodone; however it is unclear whether this is due to CPY3A4 inhibition or through its NK-1 antagonist action.^[7] Following IV administration of a 14C-labelled prodrug of aprepitant (L-758298), which is converted rapidly and completely to aprepitant, approximately 57% of the total radioactivity is excreted in the urine and 45% in feces. No unchanged substance is excreted in urine.^{[citation needed]}

One of the main features of aprepitant, and a major advantage it has over other chemotherapy-induced side-effect treatments, is its ability to selectively antagonize NK1 receptors, while having very low affinity to other common receptors such as serotonin, dopamine, and corticosteroid. It is estimated that aprepitant is at least 3,000 times more selective to NK1 receptors compared to these other enzyme transporter, ion channels.^{[citation needed]} The normal dosing of aprepitant given as 125 mg in the first day after chemotherapy and followed by 80 mg the following 2 days.

Other uses[edit]

Merck & Co. conducted clinical trials on aprepitant as a treatment of major depressive disorder, and received negative results.^[8] The company has since abandoned plans to market aprepitant as an antidepressant.

Dr. Harford-Wright of the University of Adelaide has shown in studies that the growth of brain tumors can be halted by administration of Emend, noting that "We were successful in blocking substance P from binding to the NK1 receptor, which resulted in a reduction in brain tumor growth – and it also caused cell death in the tumor cells." ^[9]

References[edit]

^ "Drug Approval Package: EMEND (Aprepitant) NDA #21-549". Retrieved 2011-04-19.
^ Structural Optimization Affording 2-(R)-(1-(R)-3,5-Bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4- (3-oxo-1,2,4-triazol-5-yl)methylmorpholine, a Potent, Orally Active, Long-Acting Morpholine Acetal Human NK-1 Receptor Antagonist. J. Med. Chem, (1998) Volume 41, Issue 23, Pages 4607-4614
^ ^a ^b Development of aprepitant, the first neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting. Annals of the New York Academy of Sciences, (2011) Volume 1222, Pages 40-48
^ Efficient Synthesis of NK1 Receptor Antagonist Aprepitant Using a Crystallization-Induced Diastereoselective Transformation. J. Am. Chem. Soc., (2003) Volume 125, Issue 8, Pages 2129-2135
^ Human positron emission tomography studies of brain neurokinin 1 receptor occupancy by aprepitant. Biological Psychiatry, (2004) Volume 55, Issue 10, Pages 1007-1012
^ Gralla R, de Wit R, Herrstedt J, Carides A, Ianus J, Guoguang-Ma J, Evans J, Horgan K (2005). "Antiemetic efficacy of the neurokinin-1 antagonist, aprepitant, plus a 5HT3 antagonist and a corticosteroid in patients receiving anthracyclines or cyclophosphamide in addition to high-dose cisplatin: analysis of combined data from two Phase III randomized clinical trials". Cancer 104 (4): 864–8. doi:10.1002/cncr.21222. PMID 15973669.
^ Walsh, S. L.; Heilig, M.; Nuzzo, P. A.; Henderson, P.; Lofwall, M. R. (2012). "Effects of the NK1 antagonist, aprepitant, on response to oral and intranasal oxycodone in prescription opioid abusers". Addiction Biology: no. doi:10.1111/j.1369-1600.2011.00419.x. edit
^ Lack of Efficacy of the Substance P (Neurokinin1 Receptor) Antagonist Aprepitant in the Treatment of Major Depressive Disorder. Biological Psychiatry, (2006) Volume 59, Issue 3, Pages 216-223
^ Brain tumor cells killed by anti-nausea drug

External links[edit]

Emend (manufacturer's website)
Aprepitant (patient information)
Emend (PDF prescription information)

UpToDate Contents

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1. そう痒症：マネージメントの概要 pruritus overview of management
2. Prevention and treatment of chemotherapy-induced nausea and vomiting
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English Journal

Chemotherapy-Induced Nausea and Vomiting Prophylaxis: Practice Within the Children's Oncology Group.

Patel P1, Robinson PD2, Orsey A3,4, Freedman JL5,6, Langevin AM7, Woods D8, Sung L9,10, Dupuis LL1,9,11.
Pediatric blood & cancer.Pediatr Blood Cancer.2016 May;63(5):887-92. doi: 10.1002/pbc.25915. Epub 2016 Jan 27.
BACKGROUND: The Children's Oncology Group (COG) has endorsed a clinical practice guideline (CPG) for acute chemotherapy-induced nausea and vomiting (CINV) prophylaxis in children with cancer. This project aims to describe current acute CINV prophylaxis practice at COG sites and the gap between this
PMID 26864262

Investigating racial disparities in use of NK1 receptor antagonists to prevent chemotherapy-induced nausea and vomiting among women with breast cancer.

Check DK1, Reeder-Hayes KE2,3, Basch EM4,2,3, Zullig LL5,6, Weinberger M4,5, Dusetzina SB4,2,7.
Breast cancer research and treatment.Breast Cancer Res Treat.2016 Apr;156(2):351-9. doi: 10.1007/s10549-016-3747-6. Epub 2016 Mar 11.
Chemotherapy-induced nausea and vomiting (CINV) is a major concern for cancer patients and, if uncontrolled, can seriously compromise quality of life (QOL) and other treatment outcomes. Because of the expense of antiemetic medications used to prevent CINV (particularly oral medications filled throug
PMID 26968396

Non-invasive insight into the release mechanisms of a poorly soluble drug from amorphous solid dispersions by confocal Raman microscopy.

Punčochová K1, Vukosavljevic B2, Hanuš J3, Beránek J4, Windbergs M5, Štěpánek F6.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft für Pharmazeutische Verfahrenstechnik e.V.Eur J Pharm Biopharm.2016 Apr;101:119-25. doi: 10.1016/j.ejpb.2016.02.001. Epub 2016 Feb 6.
In this study, we investigated the release mechanism of the poorly water soluble drug aprepitant from different amorphous solid dispersions using confocal Raman microscopy (CRM). Solid dispersions were fabricated based on either Soluplus®, as an amphiphilic copolymer and solubilizer, or on polyviny
PMID 26861928

Japanese Journal

悪性リンパ腫患者に対するCHOP療法に伴う悪心・嘔吐におけるアプレピタントの有用性に関する検討

近藤有,江尻将之,間瀬広樹,宮崎雅之,荒川裕貴,築山郁人,佐藤由美子,大島有美子,小山佐知子,牛膓沙織,横山聡,町支優和,佐々木英雄,壁谷めぐみ,久田達也,板倉由縁
日本病院薬剤師会雑誌 = Journal of Japanese Society of Hospital Pharmacists 55(3), 279-285, 2019-03
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がん薬物療法の適正化推進に向けた臨床薬学的研究

渡邊裕之,内田まやこ,増田智先
薬学雑誌 139(6), 901-909, 2019
… Guidelines on the management of chemotherapy-induced nausea and vomiting recommend aprepitant, a selective neurokinin-1 (NK-1) receptor antagonist, 5-hydroxytryptamine 3 (5-HT<sub>3</sub>) receptor antagonists, and dexamethasone as prophylactic antiemetics. … This can be countered by using aprepitant in combination with conventional antiemetics. …
NAID 130007657111

婦人科がん患者におけるパクリタキセル過敏症発現の予防に対するアプレピタント併用時のデキサメタゾン投与量の影響

松井頌明,杉原請香,玉木宏樹,西村信弘,直良浩司
日本病院薬剤師会雑誌 = Journal of Japanese Society of Hospital Pharmacists 54(11), 1365-1369, 2018-11
NAID 40021721561

「アプレピタント」

Aprepitant
Systematic (IUPAC) name
	5-([(2R,3S)-2-((R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy)-3-(4-fluorophenyl)morpholino]methyl)-1H-1,2,4-triazol-3(2H)-one
Clinical data
Trade names	Emend
AHFS/Drugs.com	monograph
MedlinePlus	a604003
Pregnancy cat.	B1 (AU) B (US)
Legal status	Prescription Only (S4) (AU) POM (UK) ℞-only (US)
Routes	Oral
Pharmacokinetic data
Bioavailability	60-65%
Protein binding	>95%
Metabolism	Hepatic (mostly CYP3A4- mediated; some contributions by CYP2C19 & CYP1A2)
Half-life	9-13 hours
Excretion	Urine (5%), faeces (86%)
Identifiers
CAS number	170729-80-3
ATC code	A04AD12
PubChem	CID 6918365
DrugBank	DB00673
ChemSpider	5293568
UNII	1NF15YR6UY
ChEBI	CHEBI:499361
ChEMBL	CHEMBL1471
Chemical data
Formula	C23H21F7N4O3
Mol. mass	534.427 g/mol
	SMILES FC(F)(F)c1cc(cc(c1)C(F)(F)F)[C@H](O[C@H]4OCCN(CC/2=N/C(=O)NN\2)[C@H]4c3ccc(F)cc3)C;
	InChI InChI=1S/C23H21F7N4O3/c1-12(14-8-15(22(25,26)27)10-16(9-14)23(28,29)30)37-20-19(13-2-4-17(24)5-3-13)34(6-7-36-20)11-18-31-21(35)33-32-18/h2-5,8-10,12,19-20H,6-7,11H2,1H3,(H2,31,32,33,35)/t12-,19+,20-/m1/s1 ; Key:ATALOFNDEOCMKK-OITMNORJSA-N ;
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