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

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 2778	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 1064	20.0 µM [IC50]
Neurokinin 3 receptor 7 Target ID: CHEMBL4429 Sources: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004196/WC500228744.pdf	Binding Agent 1064	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 8429	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
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
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

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 Page: p. 30	healthy, 21 yeras n = 1 Health Status: healthy Age Group: 21 yeras Sex: M Population Size: 1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208399Orig1s000MedR.pdf Page: p. 30	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 Page: p. 30
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 Page: p. 30	healthy, 23 years n = 1 Health Status: healthy Age Group: 23 years Sex: M Population Size: 1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208399Orig1s000MedR.pdf Page: p. 30	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 Page: p. 30
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 n = 6 Health Status: healthy Age Group: 26 years Sex: M+F Population Size: 6 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 n = 104 Health Status: unhealthy Age Group: 47.4 years Sex: F Population Size: 104 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 Page: p. 30	healthy, 54 yeras n = 1 Health Status: healthy Age Group: 54 yeras Sex: M Population Size: 1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208399Orig1s000MedR.pdf Page: p. 30	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 Page: p. 30

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inhibitor 1587	inhibitor 1767	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
BCRP 699 P-gp 1461 CYP1A2 1524 CYP2E1 882 CYP2A6 707 CYP2B6 810 CYP2C8 911 CYP2C19 1478 CYP3A4/5 278 BSEP 402	P-gp 1537 OATP1B1 406 OATP1B3 350 CYP2J2 56 CYP2B6 664 CYP2C8 693	CYP1A2 701 CYP2C8 168 CYP2C19 293 CYP3A4/5 124 CYP2B6 547

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=31 Page: 31.0	no [IC50 >100 uM]
CYP2E1 970	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=31 Page: 31.0	no [IC50 >100 uM]
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=33 Page: 33.0	no
CYP2C8 965	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=33 Page: 33.0	no
BCRP 773	inhibitor 3277 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 1001	inhibitor 3277 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 739	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=31 Page: 31.0	yes [IC50 22 uM]
CYP2C8 965	inhibitor 3277 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 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=32 Page: 32.0	yes [IC50 41 uM]
CYP3A4/5 335	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=32 Page: 32.0	yes [IC50 49 uM]
CYP2B6 1001	inhibitor 3277 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 1553	inhibitor 3277 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 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=31 Page: 31.0	yes [IC50 9.6 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=6 Page: 6.0	yes [Ki 3.4 uM]
BSEP 403	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=46 Page: 46.0	yes
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=33 Page: 33.0	yes
CYP2C19 1553	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=33 Page: 33.0	yes
CYP3A4/5 335	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=33 Page: 33.0	yes
P-gp 1650	inhibitor 3277 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 406	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=6 Page: 6.0	no
OATP1B3 350	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=6 Page: 6.0	no
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=6 Page: 6.0	no
CYP2B6 664	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=35 Page: 35.0	yes
CYP2C8 693	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=35 Page: 35.0	yes
CYP2J2 56	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206500Orig1s000ClinPharmR.pdf#page=35 Page: 35.0	yes
CYP3A4 1737	substrate 3367 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 1647	inhibitor 1626 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
Management of postoperative nausea and vomiting: focus on palonosetron.	2009 Feb	19436621
Rolapitant for the prevention of postoperative nausea and vomiting: a prospective, double-blinded, placebo-controlled randomized trial.	2011 Apr	21385988
Rolapitant (SCH 619734): a potent, selective and orally active neurokinin NK1 receptor antagonist with centrally-mediated antiemetic effects in ferrets.	2012 Jul	22497992
Rolapitant: first global approval.	2015 Nov	26467681

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.

Name

Type

Language

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 [USAN]

Common 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