ROLAPITANT

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C25H26F6N2O2
Molecular Weight	500.4766
Optical Activity	UNSPECIFIED
Defined Stereocenters	3 / 3
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

C[C@@H](OC[C@]1(CC[C@]2(CCC(=O)N2)CN1)C3=CC=CC=C3)C4=CC(=CC(=C4)C(F)(F)F)C(F)(F)F

InChI

InChIKey=FIVSJYGQAIEMOC-ZGNKEGEESA-N

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

HIDE SMILES / InChI

Molecular Formula	C25H26F6N2O2
Molecular Weight	500.4766
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	3 / 3
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206500s000lbl.pdf | http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004196/WC500228744.pdf | https://livertox.nih.gov/Rolapitant.htm

Rolapitant (VARUBI) is neurokinin 1 (NK1) receptor antagonist. Rolapitant does not have significant affinity for the NK2 or NK3 receptors. Drug 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. Most common adverse reactions are: neutropenia and hiccups at Cisplatin Based Highly Emetogenic Chemotherapy; decreased appetite, neutropenia and dizziness at Moderately Emetogenic Chemotherapy and Combinations of Anthracycline and Cyclophosphamide. Inhibition of BCRP and P-gp by rolapitant can increase plasma concentrations of the concomitant drug and potential for adverse reactions. Strong CYP3A4 Inducers (e.g., rifampin) can significantly reduce plasma concentrations of rolapitant and decrease the efficacy of VARUBI.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Neurokinin 1 receptor 35 Target ID: CHEMBL249 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206500s000lbl.pdf	Antagonist 2849	0.42 nM [Ki]
Neurokinin 2 receptor 6 Target ID: CHEMBL2327 Sources: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004196/WC500228744.pdf	Binding Agent 1076	20.0 µM [IC50]
Neurokinin 3 receptor 8 Target ID: CHEMBL4429 Sources: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004196/WC500228744.pdf	Binding Agent 1076	4.05 µM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy 3 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206500s000lbl.pdf	Secondary		Approved 8583	VARUBI Approved Use VARUBI™ 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. VARUBI is a substance P/neurokinin 1 (NK1) receptor antagonist 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. ( 1 ) Launch Date 2015

C_max

Value	Dose	Co-administered	Analyte	Population
968 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208399s000lbl.pdf	180 mg single, oral dose: 180 mg route of administration: Oral experiment type: SINGLE co-administered:		ROLAPITANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
967.69 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28906561	180 mg single, oral dose: 180 mg route of administration: Oral experiment type: SINGLE co-administered:		ROLAPITANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
118019.42 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28906561	180 mg single, oral dose: 180 mg route of administration: Oral experiment type: SINGLE co-administered:		ROLAPITANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
183 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208399s000lbl.pdf	180 mg single, oral dose: 180 mg route of administration: Oral experiment type: SINGLE co-administered:		ROLAPITANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

Doses

Dose	Population	Adverse events
20 mg single, intravenous Dose: 20 mg Route: intravenous Route: single Dose: 20 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208399Orig1s000MedR.pdf	healthy, 21 yeras Health Status: healthy Age Group: 21 yeras Sex: M Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208399Orig1s000MedR.pdf	Disc. AE: Nausea, Retching... AEs leading to discontinuation/dose reduction: Nausea (moderate, 1 patient) Retching (moderate, 1 patient) Cough (moderate, 1 patient) Hyperhidrosis (moderate, 1 patient) Abdominal pain (mild, 1 patient) Dry mouth (mild, 1 patient) Dyspnea (mild, 1 patient) Visual impairment (mild, 1 patient) Feeling hot (mild, 1 patient) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208399Orig1s000MedR.pdf
300 mg single, intravenous Highest studied dose Dose: 300 mg Route: intravenous Route: single Dose: 300 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208399Orig1s000MedR.pdf	healthy, 23 years Health Status: healthy Age Group: 23 years Sex: M Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208399Orig1s000MedR.pdf	Disc. AE: Back pain, Dizziness... AEs leading to discontinuation/dose reduction: Back pain (mild, 1 patient) Dizziness (1 patient) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208399Orig1s000MedR.pdf
720 mg single, oral Studied dose Dose: 720 mg Route: oral Route: single Dose: 720 mg Sources: https://pubmed.ncbi.nlm.nih.gov/30256537	healthy, 26 years Health Status: healthy Age Group: 26 years Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/30256537	Sources: https://pubmed.ncbi.nlm.nih.gov/30256537
200 mg single, oral Dose: 200 mg Route: oral Route: single Dose: 200 mg Sources: https://pubmed.ncbi.nlm.nih.gov/21385988	unhealthy, 47.4 years Health Status: unhealthy Age Group: 47.4 years Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/21385988	Sources: https://pubmed.ncbi.nlm.nih.gov/21385988
200 mg single, intravenous Dose: 200 mg Route: intravenous Route: single Dose: 200 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208399Orig1s000MedR.pdf	healthy, 54 yeras Health Status: healthy Age Group: 54 yeras Sex: M Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208399Orig1s000MedR.pdf	Disc. AE: Abdominal discomfort, Diarrhea... AEs leading to discontinuation/dose reduction: Abdominal discomfort (mild, 1 patient) Diarrhea (mild, 1 patient) Presyncope (mild, 1 patient) Feeling hot (mild, 1 patient) Headache (mild, 1 patient) Dizziness (mild, 1 patient) Dry mouth (mild, 1 patient) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208399Orig1s000MedR.pdf

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1946 inhibitor 2252	inhibitor 2438	inhibitor 2507	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
BCRP 910 P-gp 1741 CYP1A2 2153 CYP2E1 1060 CYP2A6 879 CYP2B6 926 CYP2C8 1057 CYP2C19 2057 CYP3A4/5 296 BSEP 550	P-gp 2052 OATP1B1 503 OATP1B3 435 CYP2J2 71 CYP2B6 776 CYP2C8 810	CYP1A2 832 CYP2C8 198 CYP2C19 329 CYP3A4/5 133 CYP2B6 669

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
CYP1A2 2333	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=31 Page: 31.0	no [IC50 >100 uM]
CYP2E1 1146	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=31 Page: 31.0	no [IC50 >100 uM]
CYP2B6 1160	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=33 Page: 33.0	no
CYP2C8 1117	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=33 Page: 33.0	no
BCRP 985	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=6 Page: 6.0	yes [IC50 0.172 uM]		yes (co-administration study) Comment: Concomitant rolapitant increased the systemic exposure to sulfasalazine, a substrate of BCRP by 2.3-fold on Day 1 and the inhibitory effect was decreased on Day 7. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=6 Page: 6.0
CYP2B6 1160	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=31 Page: 31.0	yes [IC50 13 uM]		no (co-administration study) Comment: No significant effects of rolapitant on PK of efavirenz were observed on Day 1 while a weak inhibition of efavirenz, a CYP2B6 substrate metabolism was noted on Day 7. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=31 Page: 31.0
CYP2A6 911	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=31 Page: 31.0	yes [IC50 22 uM]
CYP2C8 1117	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=31 Page: 31.0	yes [IC50 23 uM]		no (co-administration study) Comment: Single-dose rolapitant resulted in a slight increase in Cmax and AUC of repaglinide, a CYP2C8 substrate by 29% and 24%, respectively on 7 days after rolapitant dosing while did not significantly affect the systemic exposure on Day 1. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=31 Page: 31.0
CYP3A4 2633	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=32 Page: 32.0	yes [IC50 41 uM]
CYP3A4/5 357	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=32 Page: 32.0	yes [IC50 49 uM]
CYP2B6 1160	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=32 Page: 32.0	yes [IC50 8.65 uM]	SCH 720881 3
CYP2C19 2141	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=31 Page: 31.0	yes [IC50 8.7 uM]		unlikely (co-administration study) Comment: Single-dose administration of rolapitant with omeprazole resulted in an increase in Cmax and AUCi of omeprazole by 44% and 23%, respectively on Day 1 compared to those after omeprazole alone. On Day 7, Cmax and AUCi of omeprazole was 37% and 15% higher, respectively. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=31 Page: 31.0
CYP2C9 2497	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=31 Page: 31.0	yes [IC50 9.6 uM]
CYP2D6 2546	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=6 Page: 6.0	yes [Ki 3.4 uM]
BSEP 554	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=46 Page: 46.0	yes
CYP1A2 2333	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=33 Page: 33.0	yes
CYP2C19 2141	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=33 Page: 33.0	yes
CYP3A4/5 357	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=33 Page: 33.0	yes
P-gp 1932	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=6 Page: 6.0	yes		yes (co-administration study) Comment: Concomitant rolapitant increased the systemic exposure to sulfasalazine, a substrate of BCRP by 2.3-fold on Day 1 and the inhibitory effect was decreased on Day 7. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=6 Page: 6.0

Drug as victim

Target	Modality	Activity	Clinical evidence
OATP1B1 503	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=6 Page: 6.0	no
OATP1B3 435	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=6 Page: 6.0	no
P-gp 2052	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=6 Page: 6.0	no
CYP2B6 776	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=35 Page: 35.0	yes
CYP2C8 810	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=35 Page: 35.0	yes
CYP2J2 71	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=35 Page: 35.0	yes
CYP3A4 1946	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=6 Page: 6.0	yes	yes (co-administration study) Comment: Rolapitant is not recommended in patients who are on a strong CYP3A4 inducer such as rifampin for the potential loss of efficacy due to a significant decrease in systemic exposure i.e. AUC decreased by 87% with concurrent rifampin. Concurrent ketoconazole, a strong CYP3A4 inhibitor did not significantly affect systemic exposure to rolapitant. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=6 Page: 6.0

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000PharmR.pdf#page=224 Page: 224.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:90908	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:90908
ChemicalBook	CB12628366	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB12628366
MolPort	MolPort-035-942-975	https://www.molport.com/shop/molecule-link/MolPort-035-942-975
ZINC	ZINC000003816514	http://zinc15.docking.org/substances/ZINC000003816514

PubMed

Title	Date	PubMed
Rolapitant: first global approval.	2015-11	26467681
Rolapitant (SCH 619734): a potent, selective and orally active neurokinin NK1 receptor antagonist with centrally-mediated antiemetic effects in ferrets.	2012-07	22497992
Rolapitant for the prevention of postoperative nausea and vomiting: a prospective, double-blinded, placebo-controlled randomized trial.	2011-04	21385988
Management of postoperative nausea and vomiting: focus on palonosetron.	2009-02	19436621

Patents

Sample Use Guides

In Vivo Use Guide

The recommended dosage is 180 mg rolapitant administered approximately 1 to 2 hours prior to the start of chemotherapy. Administer in combination with dexamethasone and a 5-HT3 receptor. antagonist

Route of Administration: Oral

In Vitro Use Guide

In vitro rolapitant and its metabolite M19 weakly inhibited hERG (potassium) current in Mouse L-929 cells stably transfected with human hERG, with an IC50 of 1.05 uM and 5.8 uM, respectively.

Substance Class	Chemical Created by `admin` on `Mon Mar 31 18:01:33 GMT 2025` Edited by `admin` on `Mon Mar 31 18:01:33 GMT 2025`
Record UNII	NLE429IZUC
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

ROLAPITANT [USAN]

Preferred Name

English

ROLAPITANT

Official Name

English

(5S,8S)-8-{[(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy]methyl}-8-phenyl-1,7-diazaspiro[4.5]decan-2-one

Systematic Name

English

ROLAPITANT [MI]

Common Name

English

Rolapitant [WHO-DD]

Common Name

English

1,7-DIAZASPIRO(4.5)DECAN-2-ONE, 8-(((1R)-1-(3,5-BIS(TRIFLUOROMETHYL)PHENYL)ETHOXY)METHYL)-8-PHENYL-, (5S,8S)-

Systematic Name

English

rolapitant [INN]

Common Name

English

Classification Tree Code System Code

NDF-RT

N0000175786