Fosnetupitant

Identification

Summary

Fosnetupitant is a medication used in combination with others to prevent chemotherapy associated nausea and vomiting.

Brand Names

Akynzeo

Generic Name

Fosnetupitant

DrugBank Accession Number

DB14019

Background

In April 2018, the U.S. Food and Drug Administration (FDA) and the Swiss company Helsinn approved the intravenous formulation of AKYNZEO® (NEPA, a fixed antiemetic combination of fosnetupitant, 235mg, and palonosetron, 0.25mg) as an alternative treatment option for patients experiencing chemotherapy-induced nausea and vomiting ³. Fosnetupitant is the pro-drug form of netupitant ^Label.

Generally, 25% to 30% of patients with a diagnosis of cancer receive chemotherapy as a treatment modality and 70% to 80% of these patients undergoing chemotherapy treatment may experience nausea and vomiting as major side effects. Considered one of the most distressing side effects of chemotherapy, nausea and vomiting has an immense impact on the quality of life of patients receiving certain antineoplastic therapies ¹.

Type

Small Molecule

Groups

Approved

Structure

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MOLSDFPDBSMILESInChI

Similar Structures

Structure for Fosnetupitant (DB14019)

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Weight

Average: 688.608
Monoisotopic: 688.224926219

Chemical Formula

C₃₁H₃₅F₆N₄O₅P

Synonyms

• Fosnetupitant

External IDs

• 07-PNET

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Pharmacology

Indication

Indicated in combination palonosetron (as the drug Akynzeo) and dexamethasone in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy ^Label.

The following are indications listed on the EMA label ⁸:

Prevention of acute and delayed nausea and vomiting associated with highly emetogenic cisplatin-based cancer chemotherapy ⁸.

Prevention of acute and delayed nausea and vomiting associated with moderately emetogenic cancer chemotherapy ⁸.

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Used in combination to prevent	Acute delayed nausea caused by cancer chemotherapy	Regimen in combination with: Dexamethasone (DB01234), Palonosetron (DB00377)	••••••••••••
Used in combination to prevent	Acute delayed nausea caused by highly emetogenic cancer chemotherapy	Regimen in combination with: Dexamethasone (DB01234), Palonosetron (DB00377)	••••••••••••
Used in combination to prevent	Acute delayed vomiting caused by cancer chemotherapy	Regimen in combination with: Dexamethasone (DB01234), Palonosetron (DB00377)	••••••••••••
Used in combination to prevent	Acute delayed vomiting caused by highly emetogenic cancer chemotherapy	Regimen in combination with: Dexamethasone (DB01234), Palonosetron (DB00377)	••••••••••••

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Pharmacodynamics

In the combination drug, Akynzeo, palonosetron prevents nausea and vomiting during the acute phase and fosnetupitant prevents nausea and vomiting during both the acute and delayed phase after cancer chemotherapy ^Label.

Neurokinin-1 (NK-1) inhibitor drugs, such as netupitant, possess unique anxiolytic, antidepressant, and antiemetic properties ⁶.

Mechanism of action

The fosnetupitant in this drug combination is a selective P/neurokinin-1 (NK-1) receptor antagonist ^Label.

Netupitant, the active moiety of fosnetupitant, is a selective neurokinin 1 (NK1) receptor antagonist with antiemetic activity. Netupitant competitively binds to and blocks the activity of the human substance P/NK1 receptors in the central nervous system (CNS), inhibiting NK1-receptor binding of the endogenous tachykinin neuropeptide substance P (SP), which results in the prevention of chemotherapy-induced nausea and vomiting (CINV). Substance P is found in neurons of vagal afferent fibers innervating the brain-stem nucleus tractus solitarii and the area postrema, which contains the chemoreceptor trigger zone (CTZ), and may be present at high levels in response to chemotherapy. The NK-receptor is a G-protein receptor coupled to the inositol phosphate signal-transduction pathway and is found in both the nucleus tractus solitarii and the area postrema ⁷.

Netupitant demonstrated 92.5% NK1 receptor occupancy at 6 hours, with 76% occupancy at 96 hours ⁵.

Target	Actions	Organism
ANeurokinin 1 receptor	antagonist	Humans

Absorption

Following single intravenous doses of Akynzeo for injection in patients (235 mg fosnetupitant and 0.25 mg palonosetron infused in 30 minutes) or fosnetupitant in healthy subjects (235 mg fosnetupitant infused in 30 minutes), maximum concentration of fosnetupitant was achieved at the end of the 30-minute infusion ^Label.

Oral bioavailability in each species varied substantially between animals, with 42-105%, 34-83% and 37-62% in rats, dogs, and monkeys. The large variation is most likely due to the low numbers of animals used in the studies ⁸.

Volume of distribution

The mean SD volume of distribution of fosnetupitant in healthy subjects and in patients was 124 +/- 76 L and 296 +/- 535 L, respectively ^Label.

Protein binding

Netupitant is highly bound (>99%) to plasma proteins in all species ⁸.

Metabolism

Fosnetupitant is the prodrug of netupitant ^Label.

Netupitant is a moderate inhibitor and substrate of CYP3A4 ^Label.

Akynzeo should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4 systems. One dose of netupitant 300 mg significantly inhibits CYP3A4 for about 6 days. It is avisable to avoid concomitant use of drugs that are CYP3A4 substrates for one week. If not possible, consider dose reduction of CYP3A4 substrates ^Label.

In the human, rat, dog, minipig and marmoset liver microsomal incubations, two major metabolites, an N-demethylation product (M1) _and an _N-oxidation product (M2), in addition to hydroxylation products (M3), were identified in all species. CYP3A4 was found to be responsible for the oxidation of netupitant to the same metabolites observed also in the incubations with human liver microsomes. Metabolism was extensive, with the metabolites generally achieving greater concentrations than parent drug witin 24 hours. M1 and M2 exposure was similar in rat to humans, but higher in dogs, however M3 was lower in both species than in humans ⁸.

Route of elimination

After one oral dose of [14C]­netupitant, approximately one-half of the administered radioactivity was measured in the urine and feces within 120 hours of the dose. The total of 3.95% and 70.7% of the radioactive dose was measured in the urine and feces collected over 336 hours, respectively, and the average fraction of an oral dose of netupitant excreted unchanged in urine is under 1%, implying that renal clearance is not a significant route of elimination for the netupitant-related entities ^Label.

About 86.5% and 4.7% of administered radioactivity was estimated to be excreted via the feces and urine within 30 days post-dose ^Label.

Half-life

Netupitant is eliminated from the body in a multi-exponential fashion, with an apparent elimination half-life in cancer patients of 80 ± 29 hours (mean ± SD) ^Label.

Clearance

Netupitant has a mean estimated systemic clearance of 0.3 ± 9.2 L/h (mean ± SD) after a single oral dose of Akynzeo ^Label.

Adverse Effects

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Toxicity

Most common adverse reactions (≥3%) for AKYNZEO capsules are headache, asthenia, dyspepsia, fatigue, constipation and erythema ⁵.

The safety profile of Akynzeo for injection is generally similar to that seen with Aynzeo capsules ^Label, ⁵.

Currently a repeated dose safety study is ongoing in patients receiving anthracycline plus cyclophosphamide to further establish the safety profile in this setting ³.

Pathways

Not Available

Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">

Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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1,2-Benzodiazepine	The metabolism of 1,2-Benzodiazepine can be decreased when combined with Fosnetupitant.
Abametapir	The serum concentration of Fosnetupitant can be increased when it is combined with Abametapir.
Abemaciclib	The metabolism of Abemaciclib can be decreased when combined with Fosnetupitant.
Abiraterone	The metabolism of Fosnetupitant can be decreased when combined with Abiraterone.
Acalabrutinib	The metabolism of Acalabrutinib can be decreased when combined with Fosnetupitant.

Food Interactions

• Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of fosnetupitant.

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Active Moieties

Name	Kind	UNII	CAS	InChI Key
Netupitant	prodrug	7732P08TIR	290297-26-6	WAXQNWCZJDTGBU-UHFFFAOYSA-N

Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
Akynzeo	Fosnetupitant (260 mg/20mL) + Palonosetron hydrochloride (0.28 mg/20mL)	Injection	Intravenous	Helsinn Therapeutics (U.S.), Inc.	2020-06-15	Not applicable
AKYNZEO	Fosnetupitant (235 MG) + Palonosetron (0.25 MG)	Injection, powder, for solution	Intravenous	Helsinn Birex Pharmaceuticals Ltd	2020-08-05	Not applicable
Akynzeo	Fosnetupitant (260 mg/1) + Palonosetron hydrochloride (0.28 mg/1)	Injection	Intravenous	Helsinn Therapeutics (U.S.), Inc.	2018-04-20	Not applicable
Akynzeo	Fosnetupitant (260 mg/20mL) + Palonosetron hydrochloride (0.28 mg/20mL)	Injection	Intravenous	Helsinn Therapeutics (U.S.), Inc.	2023-08-01	Not applicable

Categories

Drug Categories

• Cytochrome P-450 CYP3A Inhibitors
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors (moderate)
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Substrates
• Netupitant and prodrug
• Substance P/Neurokinin-1 Receptor Antagonist

Classification

Not classified

Affected organisms

Not Available

Chemical Identifiers

UNII

T672P80L2S

CAS number

1703748-89-3

InChI Key

HZIYEEMJNBKMJH-UHFFFAOYSA-N

InChI

InChI=1S/C31H35F6N4O5P/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)

IUPAC Name

4-(5-{2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethylpropanamido}-4-(2-methylphenyl)pyridin-2-yl)-1-[(hydrogen phosphonatooxy)methyl]-1-methylpiperazin-1-ium

SMILES

CN(C(=O)C(C)(C)C1=CC(=CC(=C1)C(F)(F)F)C(F)(F)F)C1=CN=C(C=C1C1=CC=CC=C1C)N1CC[N+](C)(COP(O)([O-])=O)CC1

References

General References

1. Coyne JW: The First Oral Fixed-Dose Combination of Netupitant and Palonosetron for the Treatment of Chemotherapy-Induced Nausea and Vomiting. J Adv Pract Oncol. 2016 Jan-Feb;7(1):66-70. Epub 2016 Jan 1. [Article]
2. Navari RM: Profile of netupitant/palonosetron (NEPA) fixed dose combination and its potential in the treatment of chemotherapy-induced nausea and vomiting (CINV). Drug Des Devel Ther. 2014 Dec 17;9:155-61. doi: 10.2147/DDDT.S76158. eCollection 2015. [Article]
3. Helsinn Group announces the FDA approval of the IV formulation of AKYNZEO® (fosnetupitant/palonosetron) in the United States [Link]
4. Safety Data Sheet, Netupitant [Link]
5. Akynzeo.com [Link]
6. Antiemetic, Neurokinin-1 Receptor Blockers [Link]
7. Netupitant, PubChem [Link]
8. EMA label [File]

External Links

ChemSpider

44208829

RxNav

2044417

ChEMBL

CHEMBL3989917

Wikipedia

Netupitant/palonosetron

FDA label

Download (1 MB)

MSDS

Download (72.3 KB)

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
3	Completed	Prevention	Chemotherapy-Induced Nausea and Vomiting	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection	Intravenous
Injection, powder, for solution	Intravenous

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US9186357	No	2015-11-17	2030-11-18
US9403772	No	2016-08-02	2032-05-23
US8895586	No	2014-11-25	2032-05-23
US9908907	No	2018-03-06	2032-05-23
US8426450	No	2013-04-23	2032-05-23
US10208073	No	2019-02-19	2032-05-23
US10624911	No	2020-04-21	2037-06-02
US10717721	No	2020-07-21	2032-05-23
US10828297	No	2020-11-10	2030-12-17
US11312698	No	2012-05-23	2032-05-23
US11529362	No	2017-06-02	2037-06-02

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	1.4 mg/mL at acidic PH (2) and	Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.000216 mg/mL	ALOGPS
logP	2.57	ALOGPS
logP	0.8	Chemaxon
logS	-6.5	ALOGPS
pKa (Strongest Acidic)	-0.11	Chemaxon
pKa (Strongest Basic)	6.74	Chemaxon
Physiological Charge	-1	Chemaxon
Hydrogen Acceptor Count	6	Chemaxon
Hydrogen Donor Count	1	Chemaxon
Polar Surface Area	106.03 Å2	Chemaxon
Rotatable Bond Count	10	Chemaxon
Refractivity	175.36 m3·mol-1	Chemaxon
Polarizability	64.07 Å3	Chemaxon
Number of Rings	4	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	No	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Not Available

Chromatographic Properties

Collision Cross Sections (CCS)

Not Available

Targets

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Details1. Neurokinin 1 receptor

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Antagonist

General Function

Tachykinin receptor activity

Specific Function

This is a receptor for the tachykinin neuropeptide substance P. It is probably associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of aff...

Gene Name

TACR1

Uniprot ID

P25103

Uniprot Name

Substance-P receptor

Molecular Weight

46250.5 Da

References

1. Coyne JW: The First Oral Fixed-Dose Combination of Netupitant and Palonosetron for the Treatment of Chemotherapy-Induced Nausea and Vomiting. J Adv Pract Oncol. 2016 Jan-Feb;7(1):66-70. Epub 2016 Jan 1. [Article]
2. EMA label [File]

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Drug created at May 02, 2018 15:43 / Updated at February 21, 2021 18:54