FOSNETUPITANT CHLORIDE HYDROCHLORIDE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C31H36F6N4O5P.Cl.ClH
Molecular Weight	761.519
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure of FOSNETUPITANT CHLORIDE HYDROCHLORIDE

Structure Search

SMILES

Cl.[Cl-].CN(C(=O)C(C)(C)C1=CC(=CC(=C1)C(F)(F)F)C(F)(F)F)C2=CN=C(C=C2C3=C(C)C=CC=C3)N4CC[N+](C)(COP(O)(O)=O)CC4

InChI

InChIKey=LBTQUZNIWCWBNN-UHFFFAOYSA-N

InChI=1S/C31H35F6N4O5P.2ClH/c1-20-8-6-7-9-24(20)25-17-27(40-10-12-41(5,13-11-40)19-46-47(43,44)45)38-18-26(25)39(4)28(42)29(2,3)21-14-22(30(32,33)34)16-23(15-21)31(35,36)37;;/h6-9,14-18H,10-13,19H2,1-5H3,(H-,43,44,45);2*1H

HIDE SMILES / InChI

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/205718s002lbl.pdfhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210493s000lbl.pdf | https://www.cancer.gov/publications/dictionaries/cancer-drug/def/792159
Curator's Comment: description was created based on several sources, including http://www.ncbi.nlm.nih.gov/pubmed/?term=16332435; http://www.ncbi.nlm.nih.gov/pubmed/?term=24631949

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 Target ID: CHEMBL249 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210493s000lbl.pdf	Antagonist 2778		0.95 nM [Ki]
Substance-P receptor 8 Target ID: P25103 Gene ID: 6869.0 Gene Symbol: TACR1 Target Organism: Homo sapiens (Human) Sources: http://www.ncbi.nlm.nih.gov/pubmed/?term=25687374	Antagonist 2778		0.95 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Acute and delayed nausea and vomiting 4 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210493s000lbl.pdf	Primary		Approved 8429	AKYNZEO Approved 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. Launch Date 2018
Nausea and vomiting 19 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/205718s002lbl.pdf	Preventing		Approved 8429	Akynzeo Approved Use To treat nausea and vomiting in patients undergoing cancer chemotherapy Launch Date 2014

C_max

Value	Dose	Co-administered	Analyte	Population
434 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205718s000lbl.pdf	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:		NETUPITANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
14401 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205718s000lbl.pdf	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:		NETUPITANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
96 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205718s000lbl.pdf	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:		NETUPITANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
0.5% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205718s000lbl.pdf	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:		NETUPITANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
600 mg 1 times / day single, oral Highest studied dose Dose: 600 mg, 1 times / day Route: oral Route: single Dose: 600 mg, 1 times / day Co-administed with:: palonosetron(1.5 mg; single dose) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205718s000lbl.pdf https://pubmed.ncbi.nlm.nih.gov/25105088/	healthy, mean age 32.8 years n = 49 Health Status: healthy Age Group: mean age 32.8 years Sex: M+F Population Size: 49 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205718s000lbl.pdf https://pubmed.ncbi.nlm.nih.gov/25105088/	Other AEs: Palpitations, Constipation... Other AEs: Palpitations (2%) Constipation (4.1%) Pain in extremity (2%) Dizziness (2%) Headache (10.2%) Somnolence (2%) Anxiety (2%) Euphoric mood (2%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205718s000lbl.pdf https://pubmed.ncbi.nlm.nih.gov/25105088/
300 mg 1 times / 5 weeks multiple, oral Recommended Dose: 300 mg, 1 times / 5 weeks Route: oral Route: multiple Dose: 300 mg, 1 times / 5 weeks Co-administed with:: palonosetron(0.5 mg; prior to the start of chemotherapy cycle) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000MedR.pdf https://www.ema.europa.eu/en/documents/assessment-report/akynzeo-epar-public-assessment-report_en.pdf	unhealthy, median age 55 years n = 1033 Health Status: unhealthy Condition: cancer Age Group: median age 55 years Sex: M+F Population Size: 1033 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000MedR.pdf https://www.ema.europa.eu/en/documents/assessment-report/akynzeo-epar-public-assessment-report_en.pdf	Disc. AE: Neutropenia, Neoplasm progression... AEs leading to discontinuation/dose reduction: Neutropenia (0.5%) Neoplasm progression (0.5%) Neoplasm malignant (0.4%) Febrile neutropenia (0.2%) Leukopenia (0.2%) Thrombocytopenia (0.1%) Peritonitis (0.1%) Troponin increased (0.1%) Stomatitis (0.2%) ALT increased (0.2%) Platelet count decreased (0.2%) Angina pectoris (0.1%) Myocardial ischaemia (0.1%) Creatinine renal clearance decreased (0.1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000MedR.pdf https://www.ema.europa.eu/en/documents/assessment-report/akynzeo-epar-public-assessment-report_en.pdf
300 mg 1 times / 5 weeks multiple, oral Recommended Dose: 300 mg, 1 times / 5 weeks Route: oral Route: multiple Dose: 300 mg, 1 times / 5 weeks Co-administed with:: palonosetron(0.5 mg; prior to the start of chemotherapy cycle) Sources: https://www.ema.europa.eu/en/documents/assessment-report/akynzeo-epar-public-assessment-report_en.pdf Page: assessment-report/akynzeo-epar-public-assessment-report_en.pdf - p.130	unhealthy, median age 55 years n = 1033 Health Status: unhealthy Condition: cancer Age Group: median age 55 years Sex: M+F Population Size: 1033 Sources: https://www.ema.europa.eu/en/documents/assessment-report/akynzeo-epar-public-assessment-report_en.pdf Page: assessment-report/akynzeo-epar-public-assessment-report_en.pdf - p.130	Other AEs: Febrile neutropenia, Neutropenia... Other AEs: Febrile neutropenia (1.5%) Neutropenia (1%) Vomiting (0.6%) Anaemia (0.5%) Leukopenia (0.3%) Pneumonia (0.4%) Urinary tract infection (0.3%) Pulmonary embolism (0.2%) Cardiopulmonary failure (0.3%) Stomatitis (0.3%) Asthenia (0.2%) Neoplasm malignant (0.2%) Nausea (0.1%) Peritonitis (0.1%) Renal failure (0.1%) Abdominal pain (0.2%) Diarrhoea (0.2%) Multi-organ failure (0.2%) Pyrexia (0.2%) Femur fracture (0.2%) Neoplasm progression (0.2%) Metrorrhagia (0.2%) Haemoptysis (0.2%) Thrombocytopenia (0.1%) Electrolyte imbalance (0.1%) Convulsion (0.1%) Deep vein thrombosis (0.1%) Sources: https://www.ema.europa.eu/en/documents/assessment-report/akynzeo-epar-public-assessment-report_en.pdf Page: assessment-report/akynzeo-epar-public-assessment-report_en.pdf - p.130
300 mg 1 times / 5 weeks multiple, oral Recommended Dose: 300 mg, 1 times / 5 weeks Route: oral Route: multiple Dose: 300 mg, 1 times / 5 weeks Co-administed with:: palonosetron(0.5 mg; prior to the start of chemotherapy cycle) Sources: https://www.ema.europa.eu/en/documents/assessment-report/akynzeo-epar-public-assessment-report_en.pdf Page: assessment-report/akynzeo-epar-public-assessment-report_en.pdf - p.135	unhealthy, median age 55 years n = 1033 Health Status: unhealthy Condition: cancer Age Group: median age 55 years Sex: M+F Population Size: 1033 Sources: https://www.ema.europa.eu/en/documents/assessment-report/akynzeo-epar-public-assessment-report_en.pdf Page: assessment-report/akynzeo-epar-public-assessment-report_en.pdf - p.135	Other AEs: ALT increased, AST increased... Other AEs: ALT increased (grade 3, 1.3%) AST increased (grade 3, 0.8%) AST increased (grade 4, 0.1%) Alkaline phosphatase increased (grade 3, 0.4%) Hyperglycemia (grade 3, 7.8%) Hyperglycemia (grade 4, 0.6%) Hypokalemia (grade 3, 1.4%) Hypokalemia (grade 4, 0.4%) Hyponatremia (grade 3, 4.9%) Hyponatremia (grade 4, 0.6%) Sources: https://www.ema.europa.eu/en/documents/assessment-report/akynzeo-epar-public-assessment-report_en.pdf Page: assessment-report/akynzeo-epar-public-assessment-report_en.pdf - p.135

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inhibitor 1587	substrate 1037 inhibitor 1767 inducer 389	substrate 1217 inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2C19 1478 CYP2B6 810 CYP2C8 911 P-gp 1461 MRP2 383 BSEP 402 BCRP 699 OATP1B1 788 OATP1B3 706 OAT1 599 OAT3 642 OCT1 512 OCT2 647	CYP1A2 1054 CYP2B6 664 CYP2C8 693 CYP2C19 991 OATP1B1 406 OATP1B3 350 OCT1 327 BCRP 561 P-gp 1537	CYP1A2 701 CYP2C19 293

Drug as perpetrator

Target	Modality	Activity	Metabolite
BSEP 403	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=106 Page: 106.0	no	RO0681133 4
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=92 Page: 92.0	no
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=92 Page: 92.0	no	RO0681133 4
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=92 Page: 92.0	no	RO0713001 4
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=78 Page: 78.0	no
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=86 Page: 86.0	no	RO0713001 4
CYP2C19 1553	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=92 Page: 92.0	no
CYP2C19 1553	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=92 Page: 92.0	no	RO0681133 4
CYP2C19 1553	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=92 Page: 92.0	no	RO0713001 4
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=78 Page: 78.0	no
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=86 Page: 86.0	no	RO0713001 4
CYP2C9 1819	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=92 Page: 92.0	no
CYP2C9 1819	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=92 Page: 92.0	no	RO0681133 4
CYP2C9 1819	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=92 Page: 92.0	no	RO0713001 4
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=86 Page: 86.0	no	RO0713001 4
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=78 Page: 78.0	no
MRP2 475	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=106 Page: 106.0	no
MRP2 475	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=106 Page: 106.0	no	RO0681133 4
MRP2 475	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=106 Page: 106.0	no	RO0713001 4
OAT1 603	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=112 Page: 112.0	no
OAT1 603	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=112 Page: 112.0	no	RO0681133 4
OAT1 603	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=112 Page: 112.0	no	RO0713001 4
OAT3 644	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=112 Page: 112.0	no
OAT3 644	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=112 Page: 112.0	no	RO0681133 4
OAT3 644	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=112 Page: 112.0	no	RO0713001 4
OATP1B1 803	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=112 Page: 112.0	no
OATP1B1 803	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=112 Page: 112.0	no	RO0681133 4
OATP1B1 803	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=112 Page: 112.0	no	RO0713001 4
OATP1B3 715	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=112 Page: 112.0	no
OATP1B3 715	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=112 Page: 112.0	no	RO0681133 4
OATP1B3 715	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=112 Page: 112.0	no	RO0713001 4
OCT2 648	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=112 Page: 112.0	no	RO0681133 4
OCT2 648	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=112 Page: 112.0	no	RO0713001 4
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=106 Page: 106.0	weak [IC50 22.6 uM]	RO0713001 4
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=86 Page: 86.0	weak [IC50 23.73 uM]	RO0713001 4
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=85 Page: 85.0	weak [IC50 26.41 uM]	RO0681133 4
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=85 Page: 85.0	weak [IC50 33.26 uM]	RO0681133 4
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=86 Page: 86.0	weak [IC50 38.84 uM]	RO0713001 4
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=86 Page: 86.0	weak [IC50 39.04 uM]	RO0713001 4
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=85 Page: 85.0	weak [IC50 39.39 uM]	RO0681133 4
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=86 Page: 86.0	weak [IC50 57.45 uM]	RO0713001 4
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=106 Page: 106.0	weak [IC50 6 uM]
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=106 Page: 106.0	weak [IC50 8.6 uM]	RO0681133 4
BSEP 403	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=106 Page: 106.0	weak
BSEP 403	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=106 Page: 106.0	weak	RO0713001 4
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=78 Page: 78.0	yes [IC50 1.2 uM]	RO0681133 4
OCT1 543	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=112 Page: 112.0	yes [IC50 19 uM]	RO0681133 4
OCT2 648	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=112 Page: 112.0	yes [IC50 22.3 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=78 Page: 78.0	yes [IC50 22.6 uM]
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=85 Page: 85.0	yes [IC50 33.38 uM]
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=85 Page: 85.0	yes [IC50 4.74 uM]	RO0681133 4
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=85 Page: 85.0	yes [IC50 4.89 uM]	RO0681133 4
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=112 Page: 112.0	yes [IC50 4.95 uM]	RO0681133 4
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=85 Page: 85.0	yes [IC50 50.4 uM]
OCT1 543	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=112 Page: 112.0	yes [IC50 7.4 uM]	RO0713001 4
OCT1 543	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=112 Page: 112.0	yes [IC50 7.9 uM]
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=112 Page: 112.0	yes [IC50 8 uM]	RO0713001 4
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=85 Page: 85.0	yes [IC50 8.54 uM]	RO0681133 4
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=78 Page: 78.0	yes [Ki 1.1 uM]
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=98 Page: 98.0	yes

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
BCRP 561	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=119 Page: 119.0	no
BCRP 561	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=119 Page: 119.0	no	RO0681133 4
BCRP 561	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=119 Page: 119.0	no	RO0713001 4
CYP1A2 1054	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=73 Page: 73.0	no
CYP2B6 664	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=73 Page: 73.0	no
CYP2C19 991	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=73 Page: 73.0	no
CYP2C8 693	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=73 Page: 73.0	no
OATP1B1 406	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=117 Page: 117.0	no
OATP1B1 406	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=117 Page: 117.0	no	RO0681133 4
OATP1B1 406	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=117 Page: 117.0	no	RO0713001 4
OATP1B3 350	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=117 Page: 117.0	no
OATP1B3 350	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=117 Page: 117.0	no	RO0681133 4
OATP1B3 350	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=117 Page: 117.0	no	RO0713001 4
OCT1 327	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=117 Page: 117.0	no
OCT1 327	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=117 Page: 117.0	no	RO0681133 4
OCT1 327	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=117 Page: 117.0	no	RO0713001 4
CYP2C9 1037	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=73 Page: 73.0	yes
CYP2D6 1217	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=73 Page: 73.0	yes
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=203 Page: 203.0	yes	RO0681133 4
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=119 Page: 119.0	yes	RO0713001 4
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=73 Page: 73.0	yes		yes (co-administration study) Comment: Administration of the CYP3A4 inhibitor ketoconazole with netupitant/palonosetron FDC increased the exposure of netupitant and resulted in an AUC0-tz of 1.8 fold, AUC0-’ of 2.4 fold, and Cmax of 1.3 fold when compared to the administration of netupitant/palonosetron FDC alone. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf#page=73 Page: 73.0

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000PharmR.pdf#page=32 Page: 32.0

Sourcing

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

PubMed

Title	Date	PubMed
Novel neurokinin-1 antagonists as antiemetics for the treatment of chemotherapy-induced emesis.	2006 Apr 1	18632487
Design and synthesis of a novel, achiral class of highly potent and selective, orally active neurokinin-1 receptor antagonists.	2006 Mar 1	16332435
Efficient synthesis of novel NK1 receptor antagonists: selective 1,4-addition of grignard reagents to 6-chloronicotinic acid derivatives.	2006 Mar 3	16496986
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
Phase III safety study of intravenous NEPA: a novel fixed antiemetic combination of fosnetupitant and palonosetron in patients receiving highly emetogenic chemotherapy.	2018 Jul 1	29722791

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.

Name

Type

Language

FOSNETUPITANT CHLORIDE HYDROCHLORIDE

Official Name

English

AKYNZEO FOR INJECTION COMPONENT FOSNETUPITANT CHLORIDE HYDROCHLORIDE

Brand Name

English

FOSNETUPITANT DIHYDROCHLORIDE

Common Name

English

FOSNETUPITANT CHLORIDE [USAN RESCINDED]

Common Name

English

08-PNET

Code

English

4-[5-{2-[3,5-Bis(trifluoromethyl)phenyl]-N,2-dimethylpropanamido}-4-(2-methylphenyl)pyridin-2-yl]-1-methyl-1-[(phosphonooxy)methyl]piperazinium chloride monohydrochloride

Systematic Name

English

FOSNETUPITANT CHLORIDE HYDROCHLORIDE [USAN]

Common Name

English

PIPERAZINIUM, 4-(5-((2-(3,5-BIS(TRIFLUOROMETHYL)PHENYL)-2-METHYL-1-OXOPROPYL)METHYLAMINO)-4-(2-METHYLPHENYL)-2-PYRIDINYL)-1-METHYL-1-((PHOSPHONOOXY)METHYL)-, CHLORIDE, HYDROCHLORIDE (1:1:1)

Systematic Name

English

FOSNETUPITANT CHLORIDE HYDROCHLORIDE [JAN]

Common Name

English

Fosnetupitant chloride hydrochloride [WHO-DD]

Common Name

English

FOSNETUPITANT CHLORIDE HYDROCHLORIDE [ORANGE BOOK]

Common Name

English

FOSNETUPITANT CHLORIDE HYDROCHLORIDE COMPONENT OF AKYNZEO FOR INJECTION

Brand Name

English

Code System Code Type Description

SMS_ID

100000176235