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
- Weight
- Average: 688.608
Monoisotopic: 688.224926219 - Chemical Formula
- C31H35F6N4O5P
- Synonyms
- Fosnetupitant
- External IDs
- 07-PNET
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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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) •••••••••••• - Contraindications & Blackbox Warnings
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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 antagonistHumans - 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.
Drug Interaction Integrate drug-drug
interactions in your software1,2-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.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- 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 US AKYNZEO Fosnetupitant (235 MG) + Palonosetron (0.25 MG) Injection, powder, for solution Intravenous Helsinn Birex Pharmaceuticals Ltd 2020-08-05 Not applicable Italy Akynzeo Fosnetupitant (260 mg/1) + Palonosetron hydrochloride (0.28 mg/1) Injection Intravenous Helsinn Therapeutics (U.S.), Inc. 2018-04-20 Not applicable US Akynzeo Fosnetupitant (260 mg/20mL) + Palonosetron hydrochloride (0.28 mg/20mL) Injection Intravenous Helsinn Therapeutics (U.S.), Inc. 2023-08-01 Not applicable US
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
- 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]
- 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]
- Helsinn Group announces the FDA approval of the IV formulation of AKYNZEO® (fosnetupitant/palonosetron) in the United States [Link]
- Safety Data Sheet, Netupitant [Link]
- Akynzeo.com [Link]
- Antiemetic, Neurokinin-1 Receptor Blockers [Link]
- Netupitant, PubChem [Link]
- EMA label [File]
- External Links
- ChemSpider
- 44208829
- 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 US US9403772 No 2016-08-02 2032-05-23 US US8895586 No 2014-11-25 2032-05-23 US US9908907 No 2018-03-06 2032-05-23 US US8426450 No 2013-04-23 2032-05-23 US US10208073 No 2019-02-19 2032-05-23 US US10624911 No 2020-04-21 2037-06-02 US US10717721 No 2020-07-21 2032-05-23 US US10828297 No 2020-11-10 2030-12-17 US US11312698 No 2012-05-23 2032-05-23 US US11529362 No 2017-06-02 2037-06-02 US
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
![](https://go.drugbank.com/assets/locked/DrugTargets2-682eb846d210ae4bf33ca03febccfb57bb1c61318e699b729e5df4dfab2c5b67.png)
- 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
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- 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
- 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]
- Helsinn Group announces the FDA approval of the IV formulation of AKYNZEO® (fosnetupitant/palonosetron) in the United States [Link]
Drug created at May 02, 2018 15:43 / Updated at February 21, 2021 18:54