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

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	MOL RATIO 1 MOL RATIO (average)

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

Description

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	Antagonist 2,778	0.42 nM [Ki]
Neurokinin 2 receptor 6	Binding Agent 1,064	20.0 µM [IC50]
Neurokinin 3 receptor 7	Binding Agent 1,064	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	Secondary		Approved 8,429	VARUBI

C_max

Value	Dose	Co-administered	Analyte	Population
967.69 ng/mL	180 mg single, oral		ROLAPITANT plasma	Homo sapiens
968 ng/mL	180 mg single, oral		ROLAPITANT plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
118019.42 ng × h/mL	180 mg single, oral		ROLAPITANT plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
183 h	180 mg single, oral		ROLAPITANT plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
20 mg single, intravenous	healthy, 21 yeras n = 1	Disc. AE: Nausea, Retching...
300 mg single, intravenous Highest studied dose	healthy, 23 years n = 1	Disc. AE: Back pain, Dizziness...
720 mg single, oral Studied dose	healthy, 26 years n = 6
200 mg single, oral	unhealthy, 47.4 years n = 104
200 mg single, intravenous	healthy, 54 yeras n = 1	Disc. AE: Abdominal discomfort, Diarrhea...

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AEs

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AE	Significance	Dose	Population
Abdominal pain	mild, 1 patient Disc. AE	20 mg single, intravenous	healthy, 21 yeras n = 1
Dry mouth	mild, 1 patient Disc. AE	20 mg single, intravenous	healthy, 21 yeras n = 1
Dyspnea	mild, 1 patient Disc. AE	20 mg single, intravenous	healthy, 21 yeras n = 1
Feeling hot	mild, 1 patient Disc. AE	20 mg single, intravenous	healthy, 21 yeras n = 1
Visual impairment	mild, 1 patient Disc. AE	20 mg single, intravenous	healthy, 21 yeras n = 1

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737 inhibitor 1,587	inhibitor 1,767	inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
BCRP 699 P-gp 1,461 CYP1A2 1,524 CYP2E1 882 CYP2A6 707 CYP2B6 810 CYP2C8 911 CYP2C19 1,478 CYP3A4/5 278 BSEP 402	P-gp 1,537 OATP1B1 406 OATP1B3 350 CYP2J2 56 CYP2B6 664 CYP2C8 693	CYP1A2 701 CYP2C8 168 CYP2C19 293 CYP3A4/5 124 CYP2B6 547

Drug as perpetrator

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Target	Modality	Activity	Clinical evidence
CYP1A2 1,692	inhibitor 3,277	no [IC50 >100 uM]
CYP2E1 970	inhibitor 3,277	no [IC50 >100 uM]
CYP2B6 1,001	inducer 1,573	no
CYP2C8 965	inducer 1,573	no
BCRP 773	inhibitor 3,277	yes [IC50 0.172 uM]	yes (co-administration study)

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Drug as victim

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Target	Modality	Activity
OATP1B1 406	substrate 3,367	no
OATP1B3 350	substrate 3,367	no
P-gp 1,537	substrate 3,367	no
CYP2B6 664	substrate 3,367	yes
CYP2C8 693	substrate 3,367	yes

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626

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Sourcing

Sourcing

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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

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PubMed

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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

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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
Record UNII	NLE429IZUC
Record Status	`Validated (UNII)`
Record Version

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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

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Classification Tree

Code System

Code

Established Pharmacologic Class

NDF-RT

N0000175786

Other antiemetics

WHO-ATC

A04AD14

Agent Affecting Nervous System

NCI_THESAURUS

C267

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Code System

Code

Type

Description

NDF-RT

N0000182137

PRIMARY

Cytochrome P450 2D6 Inhibitors [MoA]

MERCK INDEX

m11844

PRIMARY

NCI_THESAURUS

C97952

PRIMARY

ChEMBL

CHEMBL3707331

PRIMARY

EPA CompTox

DTXSID90203740

PRIMARY

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Related Record

Type

Details


					PUO0521HZV

CYTOCHROME P450 3A4

METABOLIC ENZYME -> SUBSTRATE

Interaction Type:

MAJOR


					6OU487748Q

SUBSTANCE-P RECEPTOR

TARGET -> INHIBITOR

Interaction Type:

ANTAGONIST

Qualification:

Ki

Amount:

RELATIONSHIP_AMOUNT 0.66 NANOMOLAR (average)


					NLE429IZUC

ROLAPITANT

EXCRETED UNCHANGED->SUBSTANCE

Comments:

The total of 46% of the radioactive dose was recovered in urine and feces.In the pooled feces 37.8% of the dose was recovered. Rolapitant was the most prominent component accounting for 12.7% of the dose

Interaction Type:

MAJOR

Qualification:

FECAL

Amount:

RELATIONSHIP_AMOUNT 12.7 MOLE PERCENT OF AMOUNT ADMINISTERED (average)


					57O5S1QSAQ

ROLAPITANT HYDROCHLORIDE

SALT/SOLVATE -> PARENT


					J7Z9DBN8J0

ROLAPITANT HYDROCHLORIDE ANHYDROUS

SALT/SOLVATE -> PARENT

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Related Record

Type

Details


					EFL393CK3S

SCH-720881

METABOLITE ACTIVE -> PARENT

Comments:

The metabolite SCH 720881 (M19) which accounted 25% of the increased exposure to total plasma radioactivity was identified as a major circulating metabolite of rolapitant.

Interaction Type:

MAJOR

Qualification:

PLASMA

Amount:

RELATIONSHIP_AMOUNT 25 PERCENT AUC (average)

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Related Record

Type

Details


					NLE429IZUC

ROLAPITANT

ACTIVE MOIETY

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Name	Property Type	Amount
Biological Half-life	PHARMACOKINETIC	7 days (average)

Volume of Distribution	PHARMACOKINETIC	6.57 Liters/Kilogram (average)

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

Drug as perpetrator