NETUPITANT

Details

Stereochemistry	ACHIRAL
Molecular Formula	C30H32F6N4O
Molecular Weight	578.5917
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CN(C(=O)C(C)(C)C1=CC(=CC(=C1)C(F)(F)F)C(F)(F)F)C2=C(C=C(N=C2)N3CCN(C)CC3)C4=C(C)C=CC=C4

InChI

InChIKey=WAXQNWCZJDTGBU-UHFFFAOYSA-N

InChI=1S/C30H32F6N4O/c1-19-8-6-7-9-23(19)24-17-26(40-12-10-38(4)11-13-40)37-18-25(24)39(5)27(41)28(2,3)20-14-21(29(31,32)33)16-22(15-20)30(34,35)36/h6-9,14-18H,10-13H2,1-5H3

HIDE SMILES / InChI

Molecular Formula	C30H32F6N4O
Molecular Weight	578.5917
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description

Fosnetupitant is a prodrug form of netupitant. Netupitant is a selective antagonist of human substance P/neurokinin 1 (NK-1) receptors. Upon intravenous administration, fosnetupitant is converted by phosphatases to its active form. It competitively binds to and blocks the activity of NK-1 receptors in the central nervous system, by inhibiting binding of substance P (SP) to NK-1 receptors. This prevents delayed emesis, which is associated with SP secretion. AKYNZEO® is a combination of palonosetron, a serotonin-3 receptor antagonist, and netupitant (capsules for oral use) or fosnetupitant (injections for intravenous use). AKYNZEO® for injection is indicated in combination with dexamethasone in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Neurokinin 1 receptor 35	Antagonist 2,778		0.95 nM [Ki]
Substance-P receptor 8	Antagonist 2,778		0.95 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Acute and delayed nausea and vomiting 4	Primary		Approved 8,429	AKYNZEO
Nausea and vomiting 19	Preventing		Approved 8,429	Akynzeo

C_max

Value	Dose	Co-administered	Analyte	Population
434 ng/mL	300 mg single, oral		NETUPITANT plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
14401 ng × h/mL	300 mg single, oral		NETUPITANT plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
96 h	300 mg single, oral		NETUPITANT plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
0.5%	300 mg single, oral		NETUPITANT plasma	Homo sapiens

Doses

Show entries

Dose	Population	Adverse events
600 mg 1 times / day single, oral Highest studied dose	healthy, mean age 32.8 years n = 49	Other AEs: Palpitations, Constipation...
300 mg 1 times / 5 weeks multiple, oral Recommended	unhealthy, median age 55 years n = 1033	Disc. AE: Neutropenia, Neoplasm progression...
300 mg 1 times / 5 weeks multiple, oral Recommended	unhealthy, median age 55 years n = 1033	Other AEs: Febrile neutropenia, Neutropenia...
300 mg 1 times / 5 weeks multiple, oral Recommended	unhealthy, median age 55 years n = 1033	Other AEs: ALT increased, AST increased...

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AEs

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AE	Significance	Dose	Population
Headache	10.2%	600 mg 1 times / day single, oral Highest studied dose	healthy, mean age 32.8 years n = 49
Anxiety	2%	600 mg 1 times / day single, oral Highest studied dose	healthy, mean age 32.8 years n = 49
Dizziness	2%	600 mg 1 times / day single, oral Highest studied dose	healthy, mean age 32.8 years n = 49
Euphoric mood	2%	600 mg 1 times / day single, oral Highest studied dose	healthy, mean age 32.8 years n = 49
Pain in extremity	2%	600 mg 1 times / day single, oral Highest studied dose	healthy, mean age 32.8 years n = 49

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737 inhibitor 1,587	substrate 1,037 inhibitor 1,767 inducer 389	substrate 1,217 inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1,524 CYP2C19 1,478 CYP2B6 810 CYP2C8 911 P-gp 1,461 MRP2 383 BSEP 402 BCRP 699 OATP1B1 788 OATP1B3 706 OAT1 599 OAT3 642 OCT1 512 OCT2 647	CYP1A2 1,054 CYP2B6 664 CYP2C8 693 CYP2C19 991 OATP1B1 406 OATP1B3 350 OCT1 327 BCRP 561 P-gp 1,537	CYP1A2 701 CYP2C19 293

Drug as perpetrator

Show entries

Target	Modality	Activity	Metabolite
BSEP 403	inhibitor 3,277	no	RO0681133 4
CYP1A2 1,692	inducer 1,573	no
CYP1A2 1,692	inducer 1,573	no	RO0681133 4
CYP1A2 1,692	inducer 1,573	no	RO0713001 4
CYP1A2 1,692	inhibitor 3,277	no

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Drug as victim

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Target	Modality	Activity	Metabolite
BCRP 561	substrate 3,367	no
BCRP 561	substrate 3,367	no	RO0681133 4
BCRP 561	substrate 3,367	no	RO0713001 4
CYP1A2 1,054	substrate 3,367	no
CYP2B6 664	substrate 3,367	no

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:85155	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:85155
ChemicalBook	CB71483126	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB71483126
MolPort	MolPort-019-904-423	https://www.molport.com/shop/molecule-link/MolPort-019-904-423
ZINC	ZINC000011681563	http://zinc15.docking.org/substances/ZINC000011681563

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PubMed

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Title	Date	PubMed
Novel neurokinin-1 antagonists as antiemetics for the treatment of chemotherapy-induced emesis.	2006 Apr 1	18632487
A phase III study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting over repeated cycles of chemotherapy.	2014 Jul	24631949
Differential and additive suppressive effects of 5-HT3 (palonosetron)- and NK1 (netupitant)-receptor antagonists on cisplatin-induced vomiting and ERK1/2, PKA and PKC activation.	2015 Apr	25687374

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Patents

Sample Use Guides

In Vivo Use Guide

One AKYNZEO (netupitant and palonosetron) capsule administered approximately 1 hour prior to the start of chemotherapy with dexamethasone 12 mg administered orally 30 minutes prior to chemotherapy on day 1 and 8 mg orally once daily on days 2 to 4 (for highly emetogenic chemotherapy, including cisplatin based chemotherapy) or on day 1 with not necessary administration of dexamethasone on days 2 to 4 (for anthracyclines and cyclophosphamide based chemotherapy and chemotherapy not considered highly emetogenic)

Route of Administration: Oral

In Vitro Use Guide

HEK-293 cells were incubated with 5 nM [3H]-netupitant for 40 min at room temperature.