Identification

Name
Fosnetupitant
Accession Number
DB14019
Description

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
Thumb
Weight
Average: 688.608
Monoisotopic: 688.224926219
Chemical Formula
C31H35F6N4O5P
Synonyms
  • Fosnetupitant
External IDs
  • 07-PNET

Pharmacology

Pharmacology
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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.

Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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.

TargetActionsOrganism
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.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
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.
DrugInteraction
AbametapirThe serum concentration of Fosnetupitant can be increased when it is combined with Abametapir.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Fosnetupitant.
AcalabrutinibThe metabolism of Acalabrutinib can be decreased when combined with Fosnetupitant.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Fosnetupitant.
AlbendazoleThe metabolism of Albendazole can be decreased when combined with Fosnetupitant.
AlectinibThe metabolism of Alectinib can be decreased when combined with Fosnetupitant.
AlfuzosinThe metabolism of Alfuzosin can be decreased when combined with Fosnetupitant.
AlpelisibThe metabolism of Alpelisib can be decreased when combined with Fosnetupitant.
AlprazolamThe metabolism of Alprazolam can be decreased when combined with Fosnetupitant.
AminophyllineThe metabolism of Aminophylline can be decreased when combined with Fosnetupitant.
Interactions
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Food Interactions
  • Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of fosnetupitant.

Products

Products
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Active Moieties
NameKindUNIICASInChI Key
Netupitantprodrug7732P08TIR290297-26-6WAXQNWCZJDTGBU-UHFFFAOYSA-N
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
AkynzeoFosnetupitant (260 mg/1) + Palonosetron hydrochloride (0.28 mg/1)InjectionIntravenousHelsinn Therapeutics (U.S.), Inc.2018-04-20Not applicableUS flag
AkynzeoFosnetupitant (260 mg/20mL) + Palonosetron hydrochloride (0.28 mg/20mL)InjectionIntravenousHelsinn Therapeutics (U.S.), Inc.2020-06-15Not applicableUS flag

Categories

Drug Categories
Classification
Not classified

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. [PubMed:27713845]
  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. [PubMed:25552904]
  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]
ChemSpider
44208829
RxNav
2044417
ChEMBL
CHEMBL3989917
Wikipedia
Netupitant/palonosetron
FDA label
Download (1 MB)
MSDS
Download (72.3 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedPreventionChemotherapy-Induced Nausea and Vomiting (CINV)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionIntravenous
Injection, powder, for solutionIntravenous
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9186357No2015-11-172030-11-18US flag
US9403772No2016-08-022032-05-23US flag
US8895586No2014-11-252032-05-23US flag
US9908907No2018-03-062032-05-23US flag
US8426450No2013-04-232032-05-23US flag
US10208073No2019-02-192032-05-23US flag
US10624911No2017-06-022037-06-02US flag
US10717721No2012-05-232032-05-23US flag
US10828297No2010-12-172030-12-17US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility1.4 mg/mL at acidic PH (2) and Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.000216 mg/mLALOGPS
logP2.57ALOGPS
logP0.8ChemAxon
logS-6.5ALOGPS
pKa (Strongest Acidic)-0.11ChemAxon
pKa (Strongest Basic)6.74ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area106.03 Å2ChemAxon
Rotatable Bond Count10ChemAxon
Refractivity175.36 m3·mol-1ChemAxon
Polarizability64.07 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Drugtargets
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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. [PubMed:27713845]
  2. EMA label [File]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
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
References
  1. 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. [PubMed:25552904]
  2. Helsinn Group announces the FDA approval of the IV formulation of AKYNZEO® (fosnetupitant/palonosetron) in the United States [Link]

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