Fosaprepitant

Identification

Summary

Fosaprepitant is an antiemetic drug used in combination with other antiemetic agents for the prevention of acute and delayed nausea and vomiting caused by chemotherapy.

Brand Names
Emend, Focinvez
Generic Name
Fosaprepitant
DrugBank Accession Number
DB06717
Background

Fosaprepitant is an intravenously administered antiemetic drug. It is a prodrug of Aprepitant. It aids in the prevention of acute and delayed nausea and vomiting associated with chemotherapy treatment.

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 614.4066
Monoisotopic: 614.116518403
Chemical Formula
C23H22F7N4O6P
Synonyms
  • Fosaprépitant
  • Fosaprepitant
  • Fosaprepitantum
External IDs
  • L-758,298
  • L-758298

Pharmacology

Indication

Fosaprepitant is indicated in adult and pediatric patients ≥6 months of age, in combination with other antiemetic agents, for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin.1 It is also indicated for the treatment of delayed nausea and vomiting with initial and repeat courses of moderately emetogenic cancer chemotherapy.1

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Adjunct therapy in prevention ofAcute chemotherapy-induced nausea and vomiting (cinv) caused by highly emetogenic chemotherapy•••••••••••••••••• ••••••••••••••••••
Adjunct therapy in prevention ofDelayed chemotherapy-induced nausea and vomiting (cinv) caused by highly emetogenic chemotherapy•••••••••••••••••• ••••••••••••••••••
Adjunct therapy in prevention ofDelayed chemotherapy-induced nausea and vomiting (cinv) caused by moderately emetogenic chemotherapy•••••••••••••••••• ••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Fosaprepitant is a prodrug of Aprepitant. Once biologically activated, the drug acts as a substance P/neurokinin 1 (NK1) receptor antagonist which, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT3), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CI NV).

Mechanism of action

Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human Positron Emission Tomography (PET) studies with Aprepitant have shown that it crosses the blood brain barrier and occupies brain NK1 receptors. Animal and human studies show that Aprepitant augments the antiemetic activity of the 5-HT3-receptor antagonist ondansetron and the corticosteroid ethasone and inhibits both the acute and delayed phases of cisplatin induced emesis. In summary, the active form of fosaprepitant is as an NK1 antagonist which is because it blocks signals given off by NK1 receptors. This therefore decreases the likelihood of vomiting in patients experiencing.

Absorption

Not Available

Volume of distribution

Not Available

Protein binding

95% +

Metabolism

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.

Route of elimination

Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted. Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk.

Half-life

9-13 hours

Clearance

Not Available

Adverse Effects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbametapirThe serum concentration of Fosaprepitant can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Fosaprepitant can be increased when combined with Abatacept.
AbemaciclibThe metabolism of Abemaciclib can be increased when combined with Fosaprepitant.
AcalabrutinibThe metabolism of Acalabrutinib can be increased when combined with Fosaprepitant.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Fosaprepitant.
Food Interactions
  • Exercise caution with grapefruit products. Grapefruit inhibits the CYP3A4 metabolism of fosaprepitant, which may increase its serum concentration.
  • Exercise caution with St. John's Wort. This herb induces the CYP3A4 metabolism of fosaprepitant and may reduce its serum concentration.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Fosaprepitant dimeglumineD35FM8T64X265121-04-8VRQHBYGYXDWZDL-OOZCZQCLSA-N
Active Moieties
NameKindUNIICASInChI Key
Aprepitantprodrug1NF15YR6UY170729-80-3ATALOFNDEOCMKK-OITMNORJSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
EmendInjection, powder, lyophilized, for solution150 mg/5mLIntravenousMerck Sharp & Dohme LLC2017-02-03Not applicableUS flag
EmendInjection, powder, lyophilized, for solution115 mg/5mLIntravenousMerck Sharp & Dohme Limited2008-01-252012-07-31US flag
EmendInjection, powder, lyophilized, for solution150 mg/5mLIntravenousMerck Sharp & Dohme Limited2010-11-12Not applicableUS flag
Emend IVPowder, for solution115 mg / vialIntravenousMerck Ltd.2009-04-302010-10-28Canada flag
Emend IVPowder, for solution150 mg / vialIntravenousMerck Ltd.2011-04-04Not applicableCanada flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
FosaprepitantInjection, powder, lyophilized, for solution150 mg/5mLIntravenousAthenex Pharmaceutical Division, Llc.2019-11-302021-09-30US flag
FosaprepitantInjection, powder, lyophilized, for solution150 mg/5mLIntravenousNovadoz Pharmaceuticals Llc2020-05-12Not applicableUS flag
FosaprepitantInjection, powder, lyophilized, for solution150 mg/5mLIntravenousBluePoint Laboratories2022-02-02Not applicableUS flag
FosaprepitantInjection, powder, lyophilized, for solution150 mg/5mLIntravenousBaxter Healthcare Corporation2019-09-05Not applicableUS flag
FosaprepitantInjection, powder, lyophilized, for solution150 mg/5mLIntravenousMylan Institutional LLC2019-09-05Not applicableUS flag

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as phenylmorpholines. These are aromatic compounds containing a morpholine ring and a benzene ring linked to each other through a CC or a CN bond.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Oxazinanes
Sub Class
Morpholines
Direct Parent
Phenylmorpholines
Alternative Parents
Trifluoromethylbenzenes / Fluorobenzenes / Aralkylamines / Aryl fluorides / Triazoles / Heteroaromatic compounds / Trialkylamines / Oxacyclic compounds / Azacyclic compounds / Acetals
show 5 more
Substituents
1,2,4-triazole / Acetal / Alkyl fluoride / Alkyl halide / Amine / Aralkylamine / Aromatic heteromonocyclic compound / Aryl fluoride / Aryl halide / Azacycle
show 20 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
morpholines, triazoles, phosphoramide, (trifluoromethyl)benzenes, cyclic acetal (CHEBI:64321)
Affected organisms
Not Available

Chemical Identifiers

UNII
6L8OF9XRDC
CAS number
172673-20-0
InChI Key
BARDROPHSZEBKC-OITMNORJSA-N
InChI
InChI=1S/C23H22F7N4O6P/c1-12(14-8-15(22(25,26)27)10-16(9-14)23(28,29)30)40-20-19(13-2-4-17(24)5-3-13)33(6-7-39-20)11-18-31-21(35)34(32-18)41(36,37)38/h2-5,8-10,12,19-20H,6-7,11H2,1H3,(H,31,32,35)(H2,36,37,38)/t12-,19+,20-/m1/s1
IUPAC Name
(3-{[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholin-4-yl]methyl}-5-oxo-2,5-dihydro-1H-1,2,4-triazol-1-yl)phosphonic acid
SMILES
C[C@@H](O[C@H]1OCCN(CC2=NC(=O)N(N2)P(O)(O)=O)[C@H]1C1=CC=C(F)C=C1)C1=CC(=CC(=C1)C(F)(F)F)C(F)(F)F

References

Synthesis Reference

Navin Ganesh Bhatt, Nikhil Rasiklal Trivedi, Mahesh Khedekar, Sukumar Sinha, Mubeen Ahmed Khan, Ramjilal Yadav, "FOSAPREPITANT DIMEGLUMINE INTERMEDIATE, NEUTRAL FOSAPREPITANT, AND AMORPHOUS FOSAPREPITANT DIMEGLUMINE AND PROCESSES FOR THEIR PREPARATIONS." U.S. Patent US20110130366, issued June 02, 2011.

US20110130366
General References
  1. FDA Approved Drug Products: EMEND (fosaprepitant) for injection, for intravenous use [Link]
Human Metabolome Database
HMDB0015662
KEGG Drug
D06597
PubChem Compound
219090
PubChem Substance
99443269
ChemSpider
189912
RxNav
1731071
ChEBI
64321
ChEMBL
CHEMBL1199324
ZINC
ZINC000003939013
PharmGKB
PA165958390
Wikipedia
Fosaprepitant

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedPreventionChemotherapy-Induced Nausea and Vomiting1
4CompletedTreatmentNausea, Postoperative1
4CompletedTreatmentOvarian Cancer / Uterine Malignancies1
4Not Yet RecruitingPreventionBreast Cancer / Chemotherapy-Induced Nausea and Vomiting1
4Unknown StatusPreventionPost Operative Nausea and Vomiting (PONV)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntravenous150 mg
Injection, powder, lyophilized, for solutionIntravenous115 mg/5mL
Injection, powder, lyophilized, for solutionIntravenous150 mg/5mL
Powder, for solutionIntravenous115 mg / vial
SolutionIntravenous150.00 mg
Injection, powder, lyophilized, for solutionIntravenous150.0 mg
InjectionIntravenous150 mg/50mL
Injection, solutionIntravenous
Injection, powder, lyophilized, for solutionIntravenous150 mg/1
Injection, powder, lyophilized, for solutionIntravenous150 mg/1mL
Powder, for solutionIntravenous150 mg / vial
Injection, powder, for solutionParenteral150 mg
Injection, solution, concentrateIntravenous150 mg
Injection, powder, for solutionIntravenous150 MG
SolutionIntravenous245.300 mg
SolutionIntravenous245.30 mg
InjectionIntramuscular150 mg/150mg
Injection, powder, for solutionIntravenous150 mg/1vial
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US5691336Yes1997-11-252019-09-04US flag
US11065256No2021-07-202039-01-11US flag
US11065265No2021-07-202039-01-11US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00632 mg/mLALOGPS
logP2.89ALOGPS
logP2.47Chemaxon
logS-5ALOGPS
pKa (Strongest Acidic)1.05Chemaxon
pKa (Strongest Basic)4Chemaxon
Physiological Charge-2Chemaxon
Hydrogen Acceptor Count9Chemaxon
Hydrogen Donor Count3Chemaxon
Polar Surface Area123.93 Å2Chemaxon
Rotatable Bond Count9Chemaxon
Refractivity138.63 m3·mol-1Chemaxon
Polarizability49.92 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption-0.5225
Blood Brain Barrier-0.81
Caco-2 permeable-0.6534
P-glycoprotein substrateSubstrate0.8255
P-glycoprotein inhibitor INon-inhibitor0.6532
P-glycoprotein inhibitor IINon-inhibitor0.986
Renal organic cation transporterNon-inhibitor0.8583
CYP450 2C9 substrateNon-substrate0.7018
CYP450 2D6 substrateNon-substrate0.8588
CYP450 3A4 substrateSubstrate0.546
CYP450 1A2 substrateNon-inhibitor0.7539
CYP450 2C9 inhibitorNon-inhibitor0.644
CYP450 2D6 inhibitorNon-inhibitor0.8521
CYP450 2C19 inhibitorNon-inhibitor0.6705
CYP450 3A4 inhibitorInhibitor0.6258
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.5
Ames testNon AMES toxic0.5349
CarcinogenicityNon-carcinogens0.7701
BiodegradationNot ready biodegradable0.9899
Rat acute toxicity2.6064 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.5
hERG inhibition (predictor II)Inhibitor0.6528
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-0a4l-0469020000-a9d53cff50121f0ac397
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-066u-0090005000-b4e7e6af715e6d9ac1c3
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-022c-0019033000-da7676b363e17eef4348
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-00ts-0090051000-083e7ab42dc12d917c49
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-01po-1060291000-7a67dd93bd873c9e9c2c
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0f72-0961121000-2dd162ad861b339de418
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0gw1-1142961000-b3766fb947491e5e5e75
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-222.2293008
predicted
DarkChem Lite v0.1.0
[M-H]-212.59343
predicted
DeepCCS 1.0 (2019)
[M+H]+219.3647008
predicted
DarkChem Lite v0.1.0
[M+H]+214.5334
predicted
DeepCCS 1.0 (2019)
[M+Na]+219.1093008
predicted
DarkChem Lite v0.1.0
[M+Na]+220.27382
predicted
DeepCCS 1.0 (2019)

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Inducer
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. FDA Approved Drug Products: EMEND (aprepitant) oral capsules or suspension [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Dushenkov A, Kalabalik J, Carbone A, Jungsuwadee P: Drug interactions with aprepitant or fosaprepitant: Review of literature and implications for clinical practice. J Oncol Pharm Pract. 2017 Jun;23(4):296-308. doi: 10.1177/1078155216631408. Epub 2016 Feb 25. [Article]
  2. FDA Approved Drug Products: EMEND (aprepitant) oral capsules or suspension [Link]
  3. Fosaprepitant FDA label [File]

Drug created at May 17, 2010 00:16 / Updated at March 18, 2024 16:48