Rolapitant

Identification

Summary

Rolapitant is a neurokinin-1 (NK-1) receptor antagonist used in combination with other antiemetics for the prevention of delayed nausea and vomiting associated with emetogenic chemotherapy.

Brand Names

Varubi

Generic Name

Rolapitant

DrugBank Accession Number

DB09291

Background

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.

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Rolapitant (DB09291)

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Weight

Average: 500.485
Monoisotopic: 500.189847063

Chemical Formula

C₂₅H₂₆F₆N₂O₂

Synonyms

• Rolapitant

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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.

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Prophylaxis of	Delayed chemotherapy-induced nausea and vomiting		••••••••••••

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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

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).

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• Rolapitant
  • Rolapitant metabolite M19

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

Adverse Effects

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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.

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abametapir	The serum concentration of Rolapitant can be increased when it is combined with Abametapir.
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.
Afatinib	The serum concentration of Afatinib can be increased when it is combined with Rolapitant.

Food Interactions

• Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of rolapitant.
• Take with or without food.

Products

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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

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Varubi	Injection, emulsion	1.8 mg/1mL	Intravenous	GlaxoSmithLine LLC	2017-10-25	2019-01-31
Varubi	Tablet	90 mg/1	Oral	GlaxoSmithLine LLC	2015-10-07	2021-10-31
Varubi	Tablet	90 mg/1	Oral	Tersera Therapeutics Llc	2015-10-07	Not applicable
Varuby	Tablet, film coated	90 mg	Oral	Tesaro Bio Netherlands B.V.	2020-12-16	2020-03-02

Categories

ATC Codes

A04AD14 — Rolapitant

• A04AD — Other antiemetics
• A04A — ANTIEMETICS AND ANTINAUSEANTS
• A04 — ANTIEMETICS AND ANTINAUSEANTS
• A — ALIMENTARY TRACT AND METABOLISM

Drug Categories

• Alimentary Tract and Metabolism
• Antiemetics and Antinauseants
• BCRP/ABCG2 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

Chemical TaxonomyProvided by Classyfire

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 / Dialkyl ethers / Carbonyl compounds / Hydrocarbon derivatives / Organic oxides / Organofluorides / Organopnictogen compounds / Alkyl fluorides

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Substituents

2-pyrrolidone / Alkyl fluoride / Alkyl halide / Amine / Aralkylamine / Aromatic heteropolycyclic compound / Azacycle / Azaspirodecane / Benzenoid / Benzylether / Carbonyl group / Carboxamide group / Delta amino acid or derivatives / Dialkyl ether / Ether / Hydrocarbon derivative / Lactam / Monocyclic benzene moiety / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organofluoride / Organohalogen compound / Organoheterocyclic compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Phenylpiperidine / Piperidine / Pyrrolidine / Pyrrolidone / Secondary aliphatic amine / Secondary amine / Secondary carboxylic acid amide / Trifluoromethylbenzene

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Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

Not Available

Affected organisms

Not Available

Chemical Identifiers

UNII

NLE429IZUC

CAS number

552292-08-7

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

References

General References

1. Syed YY: Rolapitant: first global approval. Drugs. 2015 Nov;75(16):1941-5. doi: 10.1007/s40265-015-0485-8. [Article]
2. 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. [Article]
3. 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. [Article]
4. FDA Approved Drug Products: Varubi (rolapitant) tablets for oral use [Link]

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

FDA label

Download (315 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	3
2	Completed	Prevention	Nausea / Vomiting	1
2	Completed	Prevention	Post Operative Nausea and Vomiting (PONV)	1
2	Completed	Supportive Care	Chemo-radiation Induced Nausea and Vomiting	1
2	Completed	Treatment	Cough	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection, emulsion	Intravenous	1.8 mg/1mL
Tablet	Oral	90 mg/1
Tablet, film coated	Oral	90 MG

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
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

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	splash10-0udi-0050090000-6528038a2314dabdcc68
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0571-0090300000-6a7c654f969f87ed0906
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-002k-0080900000-dded6ebed02d137c7d81
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0f89-0051950000-511e4b9f3bda4486bb09
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-002v-2490400000-958fb13d902869e77307
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-01po-0690000000-7a652a9a06e104eb7e2a

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[M-H]-	197.23389	predicted	DeepCCS 1.0 (2019)
[M+H]+	199.55821	predicted	DeepCCS 1.0 (2019)
[M+Na]+	205.47073	predicted	DeepCCS 1.0 (2019)

Targets

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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

1. 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. [Article]

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Drug created at October 29, 2015 21:22 / Updated at February 20, 2024 23:31