APREPITANT

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C23H21F7N4O3
Molecular Weight	534.4267
Optical Activity	( + )
Defined Stereocenters	3 / 3
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

C[C@@H](O[C@H]1OCCN(CC2=NC(=O)NN2)[C@H]1C3=CC=C(F)C=C3)C4=CC(=CC(=C4)C(F)(F)F)C(F)(F)F

InChI

InChIKey=ATALOFNDEOCMKK-OITMNORJSA-N

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

HIDE SMILES / InChI

Molecular Formula	C23H21F7N4O3
Molecular Weight	534.4267
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	3 / 3
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

Fosaprepitant (Emend for Injection (US), Ivemend (EU)) 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). 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. Fosaprepitant is used for the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Neurokinin 1 receptor 35	Antagonist 2,778
Neurokinin 1 receptor 35	Antagonist 2,778

Conditions

Condition	Modality	Highest Phase	Product
Postoperative nausea and vomiting 29	Preventing	Approved 8,429	EMEND
Chemotherapy induced nausea and vomiting 10	Preventing	Approved 8,429	EMEND
Chemotherapy induced nausea and vomiting 10	Secondary	Approved 8,429	EMEND
Postoperative nausea and vomiting 29	Preventing	Approved 8,429	EMEND

C_max

Value	Dose	Analyte	Population
1354 ng/mL	125 mg single, oral	APREPITANT plasma	Homo sapiens
4.3 μg/mL	100 mg single, intravenous	APREPITANT unknown	Homo sapiens
6.1 μg/mL	130 mg single, intravenous	APREPITANT unknown	Homo sapiens

AUC

Value	Dose	Analyte	Population
44578 ng × h/mL	100 mg single, intravenous	FOSAPREPITANT plasma	Homo sapiens
27759 ng × h/mL	125 mg single, oral	APREPITANT plasma	Homo sapiens
27.8 μg × h/mL	100 mg single, intravenous	APREPITANT unknown	Homo sapiens
43.9 μg × h/mL	130 mg single, intravenous	APREPITANT unknown	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
2.2 min	100 mg single, intravenous		FOSAPREPITANT plasma	Homo sapiens
14 h	125 mg single, oral		APREPITANT plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
5%	100 mg single, intravenous		FOSAPREPITANT plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
125 mg single, oral	unhealthy, 53 years (range: 23-73 years) n = 64
130 mg single, intravenous Recommended	unhealthy, adult n = 50	Disc. AE: Dyspnea, Nerve injury, peripheral...
125 mg 1 times / day steady, oral	unhealthy n = 30	Other AEs: Constipation, Diarrhea...
125 mg 1 times / day steady, oral	unhealthy n = 63	Other AEs: Hypoglycemia, Bruising...
40 mg single, oral	unhealthy n = 34	Other AEs: Anemia, Clot blood...

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AEs

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AE	Significance	Dose	Population
Dyspnea	1 patient Disc. AE	130 mg single, intravenous Recommended	unhealthy, adult n = 50
Hyperhidrosis	1 patient Disc. AE	130 mg single, intravenous Recommended	unhealthy, adult n = 50
Nerve injury, peripheral	1 patient Disc. AE	130 mg single, intravenous Recommended	unhealthy, adult n = 50
Dyspnea	2 patients Disc. AE	130 mg single, intravenous Recommended	unhealthy, adult n = 50
Nervousness	below serious, 10 patients	125 mg 1 times / day steady, oral	unhealthy n = 30

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737 inhibitor 1,587 inducer 781	substrate 1,037 inducer 389 inhibitor 1,767	substrate 1,217 inhibitor 1,852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1,461 CYP2C19 1,478 CYP1A2 1,524 CYP2E1 882 CYP2B6 810 CYP2C8 911 CYP 111	CYP1A2 1,054 CYP2C19 991 CYP2E1 667 P-gp 1,537	P-gp 257

Drug as perpetrator

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Target	Modality	Activity	Clinical evidence
CYP3A4 1,925	inhibitor 3,277	moderate	yes (co-administration study)
CYP3A4 1,925	inducer 1,573	no
CYP 147	inhibitor 3,277	unlikely
P-gp 1,650	inducer 1,573	unlikely
P-gp 1,650	inhibitor 3,277	unlikely

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Drug as victim

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Target	Modality	Activity	Metabolite	Clinical evidence
CYP3A4 1,737	substrate 3,367	major		yes (co-administration study)
CYP3A4 1,737	substrate 3,367	major	aprepitant 3	yes (co-administration study)
CYP1A2 1,054	substrate 3,367	minor
CYP1A2 1,054	substrate 3,367	minor	aprepitant 3
CYP2C19 991	substrate 3,367	minor

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:499361	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:499361
ChEBI	CHEBI:64321	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:64321
ChemicalBook	CB11515191	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB11515191
ChemicalBook	CB32557888	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB32557888
ChemicalBook	CB7500857	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB7500857

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PubMed

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Title	Date	PubMed
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.	1998 Nov 5	9804700
Prevention of chemotherapy-induced nausea and vomiting: focus on fosaprepitant.	2008 Apr	18728837
Fosaprepitant: a neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting.	2008 Nov	18983233
Multicenter, phase II, placebo-controlled, double-blind, randomized study of aprepitant in Japanese patients receiving high-dose cisplatin.	2010 Nov	20718754
Case report: delirium due to a diltiazem-fentanyl CYP3A4 drug interaction.	2010 Nov-Dec	21112467

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Patents

Sample Use Guides

In Vivo Use Guide

Prevention of Chemotherapy Induced Nausea and Vomiting: 125 mg orally 1 hour prior to chemotherapy treatment (Day 1) and 80 mg orally once daily in the morning on Days 2 and 3. The package insert for the co-administered 5-HT3 antagonist must be consulted prior to initiation of treatment with EMEND (aprepitant capsules). Prevention of Postoperative Nausea and Vomiting: The recommended oral dosage of EMEND is 40 mg within 3 hours prior to induction of anesthesia EMEND may be taken with or without food.

Route of Administration: Oral

In Vitro Use Guide

Monocytes isolated from healthy donors were cultured for 7 days and then treated with or without aprepitant (10(-6) M) for 2 h, followed by HIV infection with drug-resistant strains for 2 h.

Substance Class	Chemical
Record UNII	1NF15YR6UY
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

APREPITANT

Official Name

English

EMEND

Brand Name

English

MK-0869

Code

English

L-754,030

Code

English

APREPITANT [EMA EPAR]

Common Name

English

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Classification Tree

Code System

Code

Other antiemetics

WHO-VATC

QA04AD12

POSTOPERATIVE COMPLICATIONS

EMA ASSESSMENT REPORTS

EMEND (AUTHORIZED: POSTOPERATIVE NAUSEA AND VOMITTING)

Established Pharmacologic Class

NDF-RT

N0000175786

SIGNS AND SYMPTOMS, DIGESTIVE

EMA ASSESSMENT REPORTS

EMEND (AUTHORIZED: VOMITTING)

Antiemetic

LIVERTOX

NBK548897

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Code System

Code

Type

Description

USAN

LL-96

PRIMARY

RS_ITEM_NUM

1041904

PRIMARY

NDF-RT

N0000185506

PRIMARY

Cytochrome P450 3A4 Inducers [MoA]

PUBCHEM

135413536

PRIMARY

IUPHAR

3490

PRIMARY

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Related Record

Type

Details


					1NF15YR6UY

APREPITANT

EXCRETED UNCHANGED

Comments:

Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted.

Amount:


					VK4SQL11C0

CYTOCHROME P450 1A2

METABOLIC ENZYME -> SUBSTRATE

Interaction Type:

MINOR

Amount:


					6OU487748Q

SUBSTANCE-P RECEPTOR

TARGET -> INHIBITOR

Amount:


					6D53G0FD0Z

PLASMA PROTEIN FRACTION (HUMAN)

BINDER->LIGAND

Interaction Type:

BINDING

Amount:

[>95] % (average)


					PUO0521HZV

CYTOCHROME P450 3A4

METABOLIC ENZYME -> SUBSTRATE

Interaction Type:

MAJOR

Amount:

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Related Record

Type

Details


					6L8OF9XRDC

FOSAPREPITANT

PRODRUG -> METABOLITE ACTIVE

Amount:


					EA5SX368WV

2-((1R)-1-(3,5-BIS(TRIFLUOROMETHYL)PHENYL)ETHOXY)-3-(4-FLUOROPHENYL) MORPHOLINE, (2R,3S)-

METABOLITE -> PARENT

Amount:


					38EA8GN2BN

(2R)-2-((1R)-1-(3,5-BIS(TRIFLUOROMETHYL)PHENYL)ETHOXY)-3-(4-FLUOROPHENYL)-5,6-DIHYDRO-2H-1,4-OXAZINE

METABOLITE -> PARENT

Amount:


					UQA9Y9TN3T

(.ALPHA.S)-.ALPHA.-(((2,5-DIHYDRO-5-OXO-1H-1,2,4-TRIAZOL-3-YL)METHYL)AMINO)-4-FLUOROBENZENEACETIC ACID

METABOLITE -> PARENT

Amount:


					32WLD5Y2TX

3H-1,2,4-TRIAZOL-3-ONE, 5-((((1S)-1-(4-FLUOROPHENYL)-2-HYDROXYETHYL)AMINO)METHYL)-1,2-DIHYDRO-

METABOLITE -> PARENT

Amount:

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Related Record

Type

Details


					CV944ASG28

APREPITANT, (-)-

IMPURITY -> PARENT

Interaction Type:

CHROMATOGRAPHIC PURITY (HPLC/UV)

Qualification:

USP

Amount:

[<0.1] PERCENT PEAK AREA (limits)


					TQ265G4AMC

APREPITANT OPEN RING METHYL ESTER

IMPURITY -> PARENT

Amount:


					ZAK2DKS46U

4-DEFLUORO-4-(P-FLUOROPHENYL) APREPITANT

IMPURITY -> PARENT

Interaction Type:

CHROMATOGRAPHIC PURITY (HPLC/UV)

Qualification:

EP

Amount:

[<0.1] PERCENT PEAK AREA (limits)


					I8ZN5S5LTS

DEFLUORO APREPITANT

IMPURITY -> PARENT

Interaction Type:

CHROMATOGRAPHIC PURITY (HPLC/UV)

Qualification:

USP

Amount:

[<0.15] PERCENT PEAK AREA (limits)


					TME8PY9FMY

3H-1,2,4-TRIAZOL-3-ONE, 5-(((2R,3S)-2-((1R)-1-(3,5-BIS(TRIFLUOROMETHYL)PHENYL)ETHOXY)-3-(4'-FLUORO(1,1'-BIPHENYL)-3-YL)-4-MORPHOLINYL)METHYL)-1,2-DIHYDRO-

IMPURITY -> PARENT

Interaction Type:

CHROMATOGRAPHIC PURITY (HPLC/UV)

Qualification:

EP

Amount:

[<0.1] PERCENT PEAK AREA (limits)

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Related Record

Type

Details


					1NF15YR6UY

APREPITANT

ACTIVE MOIETY

Amount:

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Name	Property Type	Amount
Volume of Distribution	PHARMACOKINETIC	87 LITERS (average)

Tmax	PHARMACOKINETIC	4 hours (average)

Biological Half-life	PHARMACOKINETIC	[9 to 13] hours (average)

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator