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
Thumb
Synonyms
Not Available
Product Ingredients
IngredientUNIICASInChI Key
Rolapitant hydrochlorideJ7Z9DBN8J0858102-79-1VEWAWEMXVUFANV-PVBCUUEWSA-N
Rolapitant hydrochloride monohydrate57O5S1QSAQ914462-92-3GZQWMYVDLCUBQX-WVZIYJGPSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
VarubiTablet90 mg/1OralTesaro, Inc.2015-10-07Not applicableUs
VarubiInjection, emulsion1.8 mg/1mLIntravenousTesaro, Inc.2017-10-25Not applicableUs
International/Other Brands
Varubi (Tesoro)
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

Rolapitant is indicated in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly 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.

TargetActionsOrganism
ANeurokinin-1 Receptor (NK1R)
antagonist
Human
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

Interactions

Drug Interactions
DrugInteraction
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Rolapitant.
4-MethoxyamphetamineThe metabolism of 4-Methoxyamphetamine can be decreased when combined with Rolapitant.
6-Deoxyerythronolide BThe metabolism of Rolapitant can be decreased when combined with 6-Deoxyerythronolide B.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Rolapitant.
AbemaciclibRolapitant may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
AcalabrutinibThe metabolism of Rolapitant can be decreased when combined with Acalabrutinib.
AcebutololThe metabolism of Acebutolol can be decreased when combined with Rolapitant.
AcebutololThe metabolism of Acebutolol can be decreased when combined with Rolapitant.
AcenocoumarolThe metabolism of Acenocoumarol can be decreased when combined with Rolapitant.
AcetaminophenThe metabolism of Acetaminophen can be decreased when combined with Rolapitant.
Food Interactions
Not Available

References

General References
  1. Syed YY: Rolapitant: first global approval. Drugs. 2015 Nov;75(16):1941-5. doi: 10.1007/s40265-015-0485-8. [PubMed:26467681]
  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. [PubMed:22497992]
  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. [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
FDA label
Download (315 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceChemotherapy-Induced Nausea and Vomiting (CINV)1
1CompletedPreventionChemotherapy-Induced Nausea and Vomiting (CINV)2
2CompletedPreventionNausea / Vomiting1
2CompletedTreatmentCoughing1
2RecruitingSupportive CareChemo-radiation Induced Nausea and Vomiting1
2RecruitingSupportive CareSarcomas1
3CompletedPreventionChemotherapy-Induced Nausea and Vomiting (CINV)3

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, emulsionIntravenous1.8 mg/1mL
TabletOral90 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8470842No2009-01-182029-01-18Us
US8404702No2009-10-092029-10-09Us
US8796299No2002-12-172022-12-17Us
US7049320No2003-12-082023-12-08Us
US7981905No2007-04-042027-04-04Us
US8361500No2009-10-092029-10-09Us
US7563801No2007-04-042027-04-04Us
US8178550No2007-04-042027-04-04Us
US9101615No2012-07-142032-07-14Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00166 mg/mLALOGPS
logP4.07ALOGPS
logP5ChemAxon
logS-5.5ALOGPS
pKa (Strongest Acidic)14.15ChemAxon
pKa (Strongest Basic)8.3ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area50.36 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity118.28 m3·mol-1ChemAxon
Polarizability46.2 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot 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

1. Neurokinin-1 Receptor (NK1R)
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
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. [PubMed:22497992]

Enzymes

Kind
Protein
Organism
Human
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
Human
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
Human
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
Human
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 October 21, 2018 20:40