Identification

Name
Fosnetupitant
Accession Number
DB14019
Type
Small Molecule
Groups
Approved
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].

Structure
Thumb
Synonyms
Not Available
External IDs
07-PNET
Active Moieties
NameKindUNIICASInChI Key
Netupitantprodrug7732P08TIR290297-26-6WAXQNWCZJDTGBU-UHFFFAOYSA-N
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
AkynzeoFosnetupitant (260 mg/1) + Palonosetron hydrochloride (0.28 mg/1)InjectionIntravenousHelsinn Therapeutics (U.S.), Inc2018-04-20Not applicableUs
Categories
UNII
T672P80L2S
CAS number
1703748-89-3
Weight
Average: 688.608
Monoisotopic: 688.224926219
Chemical Formula
C31H35F6N4O5P
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 phosphonooxy)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

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].

Associated Conditions
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 (NK1R)
antagonist
Human
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].

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
DrugInteraction
Acetyl sulfisoxazoleThe metabolism of Fosnetupitant can be decreased when combined with Acetyl sulfisoxazole.
AlclometasoneThe metabolism of Alclometasone can be decreased when combined with Fosnetupitant.
AlfuzosinThe metabolism of Alfuzosin can be decreased when combined with Fosnetupitant.
AmcinonideThe metabolism of Amcinonide can be decreased when combined with Fosnetupitant.
AmiodaroneThe metabolism of Fosnetupitant can be decreased when combined with Amiodarone.
AmitriptylineThe metabolism of Amitriptyline can be decreased when combined with Fosnetupitant.
ApalutamideThe serum concentration of Fosnetupitant can be decreased when it is combined with Apalutamide.
AprepitantThe serum concentration of Fosnetupitant can be increased when it is combined with Aprepitant.
AsunaprevirThe serum concentration of Asunaprevir can be increased when it is combined with Fosnetupitant.
AtazanavirThe metabolism of Fosnetupitant can be decreased when combined with Atazanavir.
Food Interactions
Not Available

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]
External Links
ChemSpider
44208829
ChEMBL
CHEMBL3989917
FDA label
Download (1 MB)
MSDS
Download (72.3 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2, 3Not Yet RecruitingSupportive CareAdverse Events / Cervical Cancers / Prophylaxis of acute chemotherapy induced nausea and vomiting1
Not AvailableNot Yet RecruitingNot AvailableProphylaxis of acute chemotherapy induced nausea and vomiting1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
InjectionIntravenous
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US9186357No2010-11-182030-11-18Us
US9403772No2012-05-232032-05-23Us
US8895586No2012-05-232032-05-23Us
US9908907No2012-05-232032-05-23Us
US8426450No2012-05-232032-05-23Us

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

Taxonomy

Classification
Not classified

Targets

1. Neurokinin-1 Receptor (NK1R)
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
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
Human
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 09:43 / Updated on September 07, 2018 03:28