Identification

Name
Fosaprepitant
Accession Number
DB06717
Type
Small Molecule
Groups
Approved
Description

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.

Structure
Thumb
Synonyms
  • Fosaprépitant
  • Fosaprepitantum
External IDs
L-758,298 / L-758298
Product Ingredients
IngredientUNIICASInChI Key
Fosaprepitant dimeglumineD35FM8T64X265121-04-8VRQHBYGYXDWZDL-OOZCZQCLSA-N
Active Moieties
NameKindUNIICASInChI Key
Aprepitantprodrug1NF15YR6UY170729-80-3ATALOFNDEOCMKK-OITMNORJSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
EmendInjection, powder, lyophilized, for solution115 mg/5mLIntravenousMerck Sharp & Dohme Limited2008-01-252012-07-31Us
EmendInjection, powder, lyophilized, for solution150 mg/5mLIntravenousMerck Sharp & Dohme Corp.2017-02-03Not applicableUs
EmendInjection, powder, lyophilized, for solution150 mg/5mLIntravenousMerck Sharp & Dohme Limited2010-11-12Not applicableUs
Emend IVPowder, for solution115 mgIntravenousMerck Ltd.2009-04-302010-10-28Canada
Emend IVPowder, for solution150 mgIntravenousMerck Ltd.2011-04-04Not applicableCanada
FosaprepitantPowder, for solution150 mgIntravenousApotex CorporationNot applicableNot applicableCanada
IvemendInjection, powder, for solution150 mgIntravenousMerck Sharp & Dohme B.V.2008-01-11Not applicableEu
IvemendInjection, powder, for solution150 mgIntravenousMerck Sharp & Dohme B.V.2008-01-11Not applicableEu
Categories
UNII
6L8OF9XRDC
CAS number
172673-20-0
Weight
Average: 614.4066
Monoisotopic: 614.116518403
Chemical Formula
C23H22F7N4O6P
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

Pharmacology

Indication

For the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy.

Associated Conditions
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
Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of Fosaprepitant can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of Fosaprepitant can be decreased when combined with (S)-Warfarin.
16-BromoepiandrosteroneThe serum concentration of 16-Bromoepiandrosterone can be increased when it is combined with Fosaprepitant.
19-norandrostenedioneThe serum concentration of 19-norandrostenedione can be increased when it is combined with Fosaprepitant.
3,5-diiodothyropropionic acidThe metabolism of Fosaprepitant can be decreased when combined with 3,5-diiodothyropropionic acid.
5-androstenedioneThe metabolism of Fosaprepitant can be decreased when combined with 5-androstenedione.
6-O-benzylguanineThe metabolism of Fosaprepitant can be decreased when combined with 6-O-benzylguanine.
AbemaciclibThe metabolism of Fosaprepitant can be decreased when combined with Abemaciclib.
AbirateroneThe metabolism of Fosaprepitant can be decreased when combined with Abiraterone.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Fosaprepitant.
Food Interactions
Not Available

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
Not Available
External Links
Human Metabolome Database
HMDB0015662
KEGG Drug
D06597
PubChem Compound
219090
PubChem Substance
99443269
ChemSpider
189912
ChEBI
64321
ChEMBL
CHEMBL1199324
PharmGKB
PA165958390
Wikipedia
Fosaprepitant
AHFS Codes
  • 56:22.92 — Miscellaneous Antiemetics
  • 56:22.32 — Neurokinin-1 Receptor Antagonists

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0CompletedSupportive CareNausea / Vomiting1
0Not Yet RecruitingBasic ScienceTraumatic Brain Injury (TBI)1
1CompletedTreatmentChemotherapy-Induced Nausea and Vomiting (CINV)2
1CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections1
1CompletedTreatmentMultiple Myeloma (MM) / Non-Hodgkin's Lymphoma (NHL) / Tumors, Solid1
1CompletedTreatmentPost-Operative Nausea and Vomiting (PONV)1
1TerminatedSupportive CareCancer, Breast / Nausea / Vomiting1
1TerminatedTreatmentChemotherapy-Induced Nausea and Vomiting (CINV)1
1, 2RecruitingTreatmentMultiple Myeloma (MM)1
1, 2TerminatedSupportive CareBreakthrough Nausea and Vomiting / Unspecified Adult Solid Tumor, Protocol Specific1
2CompletedPreventionCINV1
2CompletedPreventionLeukemia Acute Myeloid Leukemia (AML)1
2CompletedSupportive CareColorectal Cancers / Nausea and vomiting1
2CompletedSupportive CareItching1
2CompletedTreatmentAcute Myelogenous Leukaemia (AML) / Chronic Chronic myelogenous leukemia / Hematologic Diseases / Myelodysplastic Syndrome1
2CompletedTreatmentAlcohol Dependence / Alcoholism / Posttraumatic Stress Disorders1
2CompletedTreatmentCannabis Dependence1
2CompletedTreatmentChemotherapy-Induced Nausea and Vomiting (CINV)2
2CompletedTreatmentGliomas / Nausea / Vomiting1
2Not Yet RecruitingSupportive CareChemotherapy-Induced Nausea and Vomiting (CINV) / Lung Cancers1
2Not Yet RecruitingTreatmentChemotherapy-Induced Nausea and Vomiting (CINV)1
2Not Yet RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC) / Nausea / Vomiting1
2RecruitingSupportive CareSarcomas1
2RecruitingTreatmentChemotherapy-Induced Nausea and Vomiting (CINV) / Nausea / Vomiting1
2TerminatedPreventionNausea / Vomiting1
2TerminatedSupportive CareNausea and vomiting / Stage III Squamous Cell Carcinoma of the Hypopharynx / Stage III Squamous Cell Carcinoma of the Larynx / Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity / Stage III Squamous Cell Carcinoma of the Nasopharynx / Stage III Squamous Cell Carcinoma of the Oropharynx / Stage IV Squamous Cell Carcinoma of the Hypopharynx / Stage IV Squamous Cell Carcinoma of the Larynx / Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity / Stage IV Squamous Cell Carcinoma of the Nasopharynx / Stage IV Squamous Cell Carcinoma of the Oropharynx1
2TerminatedTreatmentChemotherapy-Induced Nausea and Vomiting (CINV)1
2TerminatedTreatmentCancer treatment / Nausea / Vomiting1
2Unknown StatusSupportive CareChemotherapy-Induced Nausea and Vomiting (CINV)1
2, 3CompletedPreventionPost-Operative Nausea and Vomiting (PONV)1
3CompletedPreventionChemotherapy-Induced Nausea and Vomiting (CINV)3
3CompletedSupportive CareGenital Neoplasms, Female / Nausea / Vomiting1
3CompletedTreatmentChemotherapy-Induced Nausea and Vomiting (CINV)1
3CompletedTreatmentGastroparesis1
3Not Yet RecruitingSupportive CareNeoplasms, Malignant1
3RecruitingTreatmentNon-Small Cell Lung Carcinoma (NSCLC)1
3TerminatedPreventionChemotherapy-Induced Nausea and Vomiting (CINV)1
3Unknown StatusTreatmentMultiple Myeloma (MM)1
4Active Not RecruitingTreatmentVomiting1
4CompletedPreventionNausea / Postoperative Nausea and Vomiting (PONV)1
4CompletedPreventionPost-Operative Nausea and Vomiting (PONV)2
4CompletedTreatmentCancer of the Ovary / Uterine Cancers1
4Not Yet RecruitingPreventionNausea and Vomiting, Postoperative1
4Not Yet RecruitingTreatmentPost-Operative Nausea and Vomiting (PONV)1
4RecruitingPreventionLaparoscopic Sleeve Gastrectomy / Post-Operative Nausea and Vomiting (PONV)1
4RecruitingPreventionPost-Operative Nausea and Vomiting (PONV)1
4TerminatedPreventionPost-Operative Nausea and Vomiting (PONV)1
4TerminatedTreatmentPruritus / Sezary Syndrome1
4Unknown StatusPreventionLeukemias / Malignant Lymphomas1
Not AvailableActive Not RecruitingNot AvailableLung Cancer Non-Small Cell Cancer (NSCLC)1
Not AvailableActive Not RecruitingSupportive CareChemotherapy-Induced Nausea and Vomiting (CINV) / Gastrointestinal Cancers1
Not AvailableCompletedNot AvailableChemotherapy-Induced Nausea and Vomiting (CINV)1
Not AvailableCompletedBasic ScienceNarcotic Abuse1
Not AvailableCompletedSupportive CareCancer of the Ovary / Cancer, Breast / Chronic Myeloproliferative Disorders / Gestational Trophoblastic Disease / Leukemias / Malignant Lymphomas / Multiple Myeloma and Plasma Cell Neoplasm / Myelodysplastic Syndromes / Myelodysplastic/Myeloproliferative Neoplasms / Nausea and vomiting / Neuroblastomas / Testicular germ cell tumour1
Not AvailableCompletedTreatmentAdverse Effects of Medical Drugs / Chemotherapy-Induced Nausea and Vomiting (CINV) / Effects of Chemotherapy / Sarcomas1
Not AvailableCompletedTreatmentMalignant Lymphomas1
Not AvailableCompletedTreatmentNausea / Vomiting1
Not AvailableRecruitingTreatmentCognitive Dysfunctions1
Not AvailableRecruitingTreatmentHigh Blood Pressure (Hypertension) / Type 2 Diabetes Mellitus1
Not AvailableTerminatedSupportive CareMalignant Digestive System Neoplasm / Nausea and vomiting1
Not AvailableTerminatedSupportive CareMalignant Ovarian Mixed Epithelial Tumor / Nausea and vomiting / Ovarian Brenner Tumor / Ovarian Clear Cell Cystadenocarcinoma / Ovarian Endometrioid Adenocarcinoma / Ovarian Mucinous Cystadenocarcinoma / Ovarian Seromucinous Carcinoma / Ovarian Serous Cystadenocarcinoma / Stage II Ovarian Cancer / Stage IIA Fallopian Tube Cancer / Stage IIA Ovarian Cancer / Stage IIB Fallopian Tube Cancer / Stage IIB Ovarian Cancer / Stage IIC Fallopian Tube Cancer / Stage IIC Ovarian Cancer / Stage IIIA Fallopian Tube Cancer / Stage IIIA Ovarian Cancer / Stage IIIA Primary Peritoneal Cancer / Stage IIIB Fallopian Tube Cancer / Stage IIIB Ovarian Cancer / Stage IIIB Primary Peritoneal Cancer / Stage IIIC Fallopian Tube Cancer / Stage IIIC Ovarian Cancer / Stage IIIC Primary Peritoneal Cancer / Stage IV Fallopian Tube Cancer / Stage IV Ovarian Cancer / Stage IV Primary Peritoneal Cancer / Undifferentiated Ovarian Carcinoma1
Not AvailableUnknown StatusPreventionColorectal Cancers1
Not AvailableUnknown StatusPreventionNausea / Vomiting1
Not AvailableWithdrawnPreventionCancer of the Ovary1
Not AvailableWithdrawnPreventionPost-Operative Nausea and Vomiting (PONV)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntravenous115 mg/5mL
Injection, powder, lyophilized, for solutionIntravenous150 mg/5mL
Powder, for solutionIntravenous115 mg
Powder, for solutionIntravenous150 mg
Injection, powder, for solutionIntravenous150 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5691336Yes1999-09-042019-09-04Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00632 mg/mLALOGPS
logP2.89ALOGPS
logP2.4ChemAxon
logS-5ALOGPS
pKa (Strongest Acidic)1.02ChemAxon
pKa (Strongest Basic)5.69ChemAxon
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-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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
Phenylmorpholine / Trifluoromethylbenzene / Fluorobenzene / Halobenzene / Aralkylamine / Aryl fluoride / Aryl halide / Monocyclic benzene moiety / Benzenoid / Azole
show 20 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
morpholines, triazoles, phosphoramide, (trifluoromethyl)benzenes, cyclic acetal (CHEBI:64321)

Enzymes

Kind
Protein
Organism
Human
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
Kind
Protein
Organism
Human
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. [PubMed:26921085]
  2. Fosaprepitant FDA label [File]

Drug created on May 16, 2010 18:16 / Updated on October 21, 2018 20:34