Identification
- Name
- Rolapitant
- Accession Number
- DB09291
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Description
Rolapitant is a potent, highly selective, long-acting Neurokinin-1 (NK-1) receptor antagonist approved for the prevention of delayed chemotherapy-induced nausea and vomiting (CINV) in adults. Delayed-phase CINV typically occurs >24 hours after chemotherapy treatment and is principally mediated by Neurokinin-1 and its ligand Substance P, which is released in the gut following chemotherapy administration. Neurokinin-1 is also known as Tachykinin Receptor 1 (TACR1), Neurokinin 1 Receptor (NK1R), and Substance P Receptor (SPR). By blocking Substance P from interacting with NK-1 receptors in the gut and the central nervous system, rolapitant prevents late-phase CINV. Unlike other available NK-1 receptor antagonists, rolapitant is not an inhibitor of Cytochrome P450 enzyme CYP3A4 and has a long elimination half-life, allowing a single dose to prevent both acute and late-phase CINV during the first 120 hours post-chemotherapy.
- Structure
Structure for Rolapitant (DB09291)
- Synonyms
- Rolapitant
- Product Ingredients
Ingredient UNII CAS InChI Key Rolapitant hydrochloride J7Z9DBN8J0 858102-79-1 VEWAWEMXVUFANV-PVBCUUEWSA-N Rolapitant hydrochloride monohydrate 57O5S1QSAQ 914462-92-3 GZQWMYVDLCUBQX-WVZIYJGPSA-N - Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Unlock Additional DataVarubi Injection, emulsion 1.8 mg/1mL Intravenous Tesaro, Inc. 2017-10-25 Not applicable US 
Varubi Tablet 90 mg/1 Oral Tesaro, Inc. 2015-10-07 Not applicable US Varubi Tablet 90 mg/1 Oral Tersera Therapeutics Llc 2015-10-07 Not applicable US Additional Data Available- Application NumberApplication Number
A unique ID assigned by the FDA when a product is submitted for approval by the labeller.
Learn more - Product CodeProduct Code
A governmentally-recognized ID which uniquely identifies the product within its regulatory market.
Learn more
- Categories
- Alimentary Tract and Metabolism
- Antiemetics and Antinauseants
- BCRP/ABCG2 Inhibitors
- Breast Cancer Resistance Protein Inhibitors
- Cytochrome P-450 CYP2D6 Inhibitors
- Cytochrome P-450 CYP2D6 Inhibitors (moderate)
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Neurokinin 1 Antagonists
- Neurokinin-1 Receptor Antagonists
- Neurotransmitter Agents
- P-glycoprotein inhibitors
- Substance P/Neurokinin-1 Receptor Antagonist
- UNII
- NLE429IZUC
- CAS number
- 552292-08-7
- Weight
- Average: 500.485
Monoisotopic: 500.189847063 - Chemical Formula
- C25H26F6N2O2
- InChI Key
- FIVSJYGQAIEMOC-ZGNKEGEESA-N
- InChI
- InChI=1S/C25H26F6N2O2/c1-16(17-11-19(24(26,27)28)13-20(12-17)25(29,30)31)35-15-23(18-5-3-2-4-6-18)10-9-22(14-32-23)8-7-21(34)33-22/h2-6,11-13,16,32H,7-10,14-15H2,1H3,(H,33,34)/t16-,22-,23-/m1/s1
- IUPAC Name
- (5S,8S)-8-{[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]methyl}-8-phenyl-1,7-diazaspiro[4.5]decan-2-one
- SMILES
- C[C@@H](OC[C@]1(CC[C@]2(CCC(=O)N2)CN1)C1=CC=CC=C1)C1=CC(=CC(=C1)C(F)(F)F)C(F)(F)F
Pharmacology
- Indication
This drug is indicated in adults in combination with other antiemetics for the prevention of delayed nausea and vomiting associated with emetogenic chemotherapy.
- Associated Conditions
- Pharmacodynamics
- Not Available
- Mechanism of action
Rolapitant is an orally active, highly selective Neurokinin-1 Receptor (NK1R) antagonist. NK1 receptors are located primarily in the gut and central nervous system and are activated by Substance P following chemotherapy administration. By binding to the NK1 receptor, rolapitant prevents binding of its ligand Substance P, which is released in the gut following chemotherapy administration.
Target Actions Organism ANeurokinin 1 receptor antagonistHumans - Absorption
Following administration of rolapitant, plasma concentrations reached peak levels in about 4 hours.
- Volume of distribution
460 L
- Protein binding
Rolapitant is 99.8% bound to human plasma protein.
- Metabolism
Rolapitant is metabolized primarily by Cytochrome P450 enzyme 3A4 (CYP3A4) to its major active and circulating metabolite M19 (C4-pyrrolidine-hydroxylated rolapitant).
- Route of elimination
Rolapitant was found to be 14.2% renally excreted and 73% fecally excreted. Of the fecally excreted compounds
- Half life
Mean terminal half life ranged from 169 to 183 hours (~7 days).
- Clearance
0.96 L/hour
- Toxicity
Most common adverse reactions occurring in >3% of patients receiving moderately emetogenic chemotherapy and combinations of anthracycline and cyclophosphamide included decreased appetite, neutropenia, dizziness, dyspepsia, urinary tract infection, stomatitis, and anemia. Most common adverse reactions occurring in patients receiving cisplatin-based highly emetogenic chemotherapy included neutropenia, hiccups, and abdominal pain.
- Affected organisms
- Not Available
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.
Learn moreStructured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.
Learn moreStructured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.
Learn moreInteractions
- 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.
Drug Interaction Unlock Additional Data4-Methoxyamphetamine The metabolism of 4-Methoxyamphetamine can be decreased when combined with Rolapitant. 5-methoxy-N,N-dimethyltryptamine The metabolism of 5-methoxy-N,N-dimethyltryptamine can be decreased when combined with Rolapitant. Abemaciclib Rolapitant may decrease the excretion rate of Abemaciclib which could result in a higher serum level. Acebutolol The metabolism of Acebutolol can be decreased when combined with Rolapitant. Acetaminophen The metabolism of Acetaminophen can be decreased when combined with Rolapitant. Acetyldigoxin Rolapitant may decrease the excretion rate of Acetyldigoxin which could result in a higher serum level. Afatinib The serum concentration of Afatinib can be increased when it is combined with Rolapitant. Allopurinol Rolapitant may decrease the excretion rate of Allopurinol which could result in a higher serum level. Almotriptan The metabolism of Almotriptan can be decreased when combined with Rolapitant. Alogliptin The metabolism of Alogliptin can be decreased when combined with Rolapitant. Additional Data Available- Extended DescriptionExtended Description
Extended description of the mechanism of action and particular properties of each drug interaction.
Learn more - Severity
- Evidence Level
- ActionAction
An effect category for each drug interaction. Know how this interaction affects the subject drug.
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- Food Interactions
- Not Available
References
- General References
- Syed YY: Rolapitant: first global approval. Drugs. 2015 Nov;75(16):1941-5. doi: 10.1007/s40265-015-0485-8. [PubMed:26467681]
- Duffy RA, Morgan C, Naylor R, Higgins GA, Varty GB, Lachowicz JE, Parker EM: Rolapitant (SCH 619734): a potent, selective and orally active neurokinin NK1 receptor antagonist with centrally-mediated antiemetic effects in ferrets. Pharmacol Biochem Behav. 2012 Jul;102(1):95-100. doi: 10.1016/j.pbb.2012.03.021. Epub 2012 Mar 31. [PubMed:22497992]
- Gan TJ, Gu J, Singla N, Chung F, Pearman MH, Bergese SD, Habib AS, Candiotti KA, Mo Y, Huyck S, Creed MR, Cantillon M: Rolapitant for the prevention of postoperative nausea and vomiting: a prospective, double-blinded, placebo-controlled randomized trial. Anesth Analg. 2011 Apr;112(4):804-12. doi: 10.1213/ANE.0b013e31820886c3. Epub 2011 Mar 8. [PubMed:21385988]
- External Links
- KEGG Drug
- D10742
- PubChem Compound
- 10311306
- PubChem Substance
- 310265183
- ChemSpider
- 8486772
- RxNav
- 1665496
- ChEBI
- 90908
- ChEMBL
- CHEMBL3707331
- ZINC
- ZINC000003816514
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Rolapitant
- ATC Codes
- A04AD14 — Rolapitant
- FDA label
- Download (315 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 1 Completed Basic Science Chemotherapy-Induced Nausea and Vomiting (CINV) 1 1 Completed Prevention Chemotherapy-Induced Nausea and Vomiting (CINV) 2 2 Completed Prevention Nausea / Vomiting 1 2 Completed Prevention Post Operative Nausea and Vomiting (PONV) 1 2 Completed Treatment Coughing 1 2 Recruiting Supportive Care Chemo-radiation Induced Nausea and Vomiting 1 2 Recruiting Supportive Care Locally Advanced Sarcoma / Sarcomas 1 2 Withdrawn Treatment Germ Cell Tumors 1 3 Completed Prevention Chemotherapy-Induced Nausea and Vomiting (CINV) 3
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage forms
Form Route Strength Injection, emulsion Intravenous 1.8 mg/1mL Tablet Oral 90 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Unlock Additional DataUS8470842 No 2013-06-25 2029-01-18 US US8404702 No 2013-03-26 2029-10-09 US US8796299 No 2014-08-05 2022-12-17 US US7049320 No 2006-05-23 2023-12-08 US US7981905 No 2011-07-19 2027-04-04 US US8361500 No 2013-01-29 2029-10-09 US US7563801 No 2009-07-21 2027-04-04 US US8178550 No 2012-05-15 2027-04-04 US US9101615 No 2015-08-11 2032-07-14 US Additional Data Available- Filed On
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.00166 mg/mL ALOGPS logP 4.07 ALOGPS logP 5 ChemAxon logS -5.5 ALOGPS pKa (Strongest Acidic) 14.15 ChemAxon pKa (Strongest Basic) 8.3 ChemAxon Physiological Charge 1 ChemAxon Hydrogen Acceptor Count 3 ChemAxon Hydrogen Donor Count 2 ChemAxon Polar Surface Area 50.36 Å2 ChemAxon Rotatable Bond Count 7 ChemAxon Refractivity 118.28 m3·mol-1 ChemAxon Polarizability 46.18 Å3 ChemAxon Number of Rings 4 ChemAxon Bioavailability 0 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
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available
Taxonomy
- Description
- This compound belongs to the class of organic compounds known as delta amino acids and derivatives. These are compounds containing a carboxylic acid group and an amino group at the C5 carbon atom.
- Kingdom
- Organic compounds
- Super Class
- Organic acids and derivatives
- Class
- Carboxylic acids and derivatives
- Sub Class
- Amino acids, peptides, and analogues
- Direct Parent
- Delta amino acids and derivatives
- Alternative Parents
- Phenylpiperidines / Trifluoromethylbenzenes / Azaspirodecane derivatives / Benzylethers / Aralkylamines / Pyrrolidine-2-ones / Secondary carboxylic acid amides / Lactams / Azacyclic compounds / Dialkylamines show 7 more
- Substituents
- Delta amino acid or derivatives / Phenylpiperidine / Azaspirodecane / Trifluoromethylbenzene / Benzylether / Aralkylamine / Monocyclic benzene moiety / Piperidine / Benzenoid / Pyrrolidone show 25 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
Targets
- 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
- Duffy RA, Morgan C, Naylor R, Higgins GA, Varty GB, Lachowicz JE, Parker EM: Rolapitant (SCH 619734): a potent, selective and orally active neurokinin NK1 receptor antagonist with centrally-mediated antiemetic effects in ferrets. Pharmacol Biochem Behav. 2012 Jul;102(1):95-100. doi: 10.1016/j.pbb.2012.03.021. Epub 2012 Mar 31. [PubMed:22497992]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Steroid hydroxylase activity
- Specific Function
- Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
- Gene Name
- CYP2D6
- Uniprot ID
- P10635
- Uniprot Name
- Cytochrome P450 2D6
- Molecular Weight
- 55768.94 Da
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- 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
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- ATP-binding cassette sub-family G member 2
- Molecular Weight
- 72313.47 Da
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- Multidrug resistance protein 1
- Molecular Weight
- 141477.255 Da
Drug created on October 29, 2015 15:22 / Updated on March 30, 2020 21:54
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