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

Similar Structures

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
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Varubi	Tablet	90 mg/1	Oral	Tersera Therapeutics Llc	2015-10-07	Not applicable
Varubi	Injection, emulsion	1.8 mg/1mL	Intravenous	Tesaro, Inc.	2017-10-25	Not applicable
Varubi	Tablet	90 mg/1	Oral	Tesaro, Inc.	2015-10-07	Not applicable

Additional Data Available

Application Number

A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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Product Code

A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

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

Delayed chemotherapy induced naused and vomiting

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	antagonist	Humans

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Additional Data Available

Adverse Effects

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

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Contraindications

Structured 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.

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Additional Data Available

Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

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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).

Rolapitant
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

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.

Drug	Interaction
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4-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	The serum concentration of Abemaciclib can be increased when it is combined with Rolapitant.
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.
Acetylsalicylic acid	The serum concentration of Acetylsalicylic acid can be increased when it is combined with Rolapitant.
Afatinib	The serum concentration of Afatinib can be increased when it is combined with Rolapitant.
Aldosterone	The serum concentration of Aldosterone can be increased when it is combined with Rolapitant.
Alitretinoin	The serum concentration of Alitretinoin can be increased when it is combined with Rolapitant.

Additional Data Available

Extended Description

Extended description of the mechanism of action and particular properties of each drug interaction.

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Severity

A severity rating for each drug interaction, from minor to major.

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Evidence Level

A rating for the strength of the evidence supporting each drug interaction.

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Action

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
ChEBI: 90908
ChEMBL: CHEMBL3707331
RxList: RxList Drug Page
Drugs.com: Drugs.com Drug Page
Wikipedia: Rolapitant

ATC Codes

A04AD14 — Rolapitant

FDA label

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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 Data
US8470842	No	2013-06-25	2029-01-18
US8404702	No	2013-03-26	2029-10-09
US8796299	No	2014-08-05	2022-12-17
US7049320	No	2006-05-23	2023-12-08
US7981905	No	2011-07-19	2027-04-04
US8361500	No	2013-01-29	2029-10-09
US7563801	No	2009-07-21	2027-04-04
US8178550	No	2012-05-15	2027-04-04
US9101615	No	2015-08-11	2032-07-14

Additional Data Available

Filed On

The date on which a patent was filed with the relevant government.

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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
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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

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

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

Details1. Cytochrome P450 2D6

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

Details2. Cytochrome P450 3A4

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

Details1. ATP-binding cassette sub-family G member 2

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

Details2. P-glycoprotein 1

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 November 12, 2019 22:57

Rolapitant

Identification

Structure for Rolapitant (DB09291)

Pharmacology

Interactions

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Taxonomy

Targets

References

Enzymes

Transporters