U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C25H26F6N2O2
Molecular Weight 500.4775
Optical Activity UNSPECIFIED
Defined Stereocenters 3 / 3
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of ROLAPITANT

SMILES

C[C@]([H])(c1cc(cc(c1)C(F)(F)F)C(F)(F)F)OC[C@]2(CC[C@]3(CCC(=N3)O)CN2)c4ccccc4

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 500.4775
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 3 / 3
E/Z Centers 0
Optical Activity UNSPECIFIED

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.

Approval Year

TargetsConditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Secondary
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

1.4410656E12
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
967.69 ng/mL
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
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

AUC

ValueDoseCo-administeredAnalytePopulation
118019.42 ng × h/mL
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
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
183 h
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

Doses

DosePopulationAdverse events​
20 mg single, intravenous
Dose: 20 mg
Route: intravenous
Route: single
Dose: 20 mg
Sources: Page: p. 30
healthy, 21 yeras
n = 1
Health Status: healthy
Age Group: 21 yeras
Sex: M
Population Size: 1
Sources: 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: Page: p. 30
300 mg single, intravenous
Highest studied dose
Dose: 300 mg
Route: intravenous
Route: single
Dose: 300 mg
Sources: Page: p. 30
healthy, 23 years
n = 1
Health Status: healthy
Age Group: 23 years
Sex: M
Population Size: 1
Sources: Page: p. 30
Disc. AE: Back pain, Dizziness...
AEs leading to
discontinuation/dose reduction:
Back pain (mild, 1 patient)
Dizziness (1 patient)
Sources: Page: p. 30
720 mg single, oral
Studied dose
Dose: 720 mg
Route: oral
Route: single
Dose: 720 mg
Sources:
healthy, 26 years
n = 6
Health Status: healthy
Age Group: 26 years
Sex: M+F
Population Size: 6
Sources:
200 mg single, oral
Dose: 200 mg
Route: oral
Route: single
Dose: 200 mg
Sources:
unhealthy, 47.4 years
n = 104
Health Status: unhealthy
Age Group: 47.4 years
Sex: F
Population Size: 104
Sources:
200 mg single, intravenous
Dose: 200 mg
Route: intravenous
Route: single
Dose: 200 mg
Sources: Page: p. 30
healthy, 54 yeras
n = 1
Health Status: healthy
Age Group: 54 yeras
Sex: M
Population Size: 1
Sources: 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: Page: p. 30
AEs

AEs

AESignificanceDosePopulation
Abdominal pain mild, 1 patient
Disc. AE
20 mg single, intravenous
Dose: 20 mg
Route: intravenous
Route: single
Dose: 20 mg
Sources: Page: p. 30
healthy, 21 yeras
n = 1
Health Status: healthy
Age Group: 21 yeras
Sex: M
Population Size: 1
Sources: Page: p. 30
Dry mouth mild, 1 patient
Disc. AE
20 mg single, intravenous
Dose: 20 mg
Route: intravenous
Route: single
Dose: 20 mg
Sources: Page: p. 30
healthy, 21 yeras
n = 1
Health Status: healthy
Age Group: 21 yeras
Sex: M
Population Size: 1
Sources: Page: p. 30
Dyspnea mild, 1 patient
Disc. AE
20 mg single, intravenous
Dose: 20 mg
Route: intravenous
Route: single
Dose: 20 mg
Sources: Page: p. 30
healthy, 21 yeras
n = 1
Health Status: healthy
Age Group: 21 yeras
Sex: M
Population Size: 1
Sources: Page: p. 30
Feeling hot mild, 1 patient
Disc. AE
20 mg single, intravenous
Dose: 20 mg
Route: intravenous
Route: single
Dose: 20 mg
Sources: Page: p. 30
healthy, 21 yeras
n = 1
Health Status: healthy
Age Group: 21 yeras
Sex: M
Population Size: 1
Sources: Page: p. 30
Visual impairment mild, 1 patient
Disc. AE
20 mg single, intravenous
Dose: 20 mg
Route: intravenous
Route: single
Dose: 20 mg
Sources: Page: p. 30
healthy, 21 yeras
n = 1
Health Status: healthy
Age Group: 21 yeras
Sex: M
Population Size: 1
Sources: Page: p. 30
Cough moderate, 1 patient
Disc. AE
20 mg single, intravenous
Dose: 20 mg
Route: intravenous
Route: single
Dose: 20 mg
Sources: Page: p. 30
healthy, 21 yeras
n = 1
Health Status: healthy
Age Group: 21 yeras
Sex: M
Population Size: 1
Sources: Page: p. 30
Hyperhidrosis moderate, 1 patient
Disc. AE
20 mg single, intravenous
Dose: 20 mg
Route: intravenous
Route: single
Dose: 20 mg
Sources: Page: p. 30
healthy, 21 yeras
n = 1
Health Status: healthy
Age Group: 21 yeras
Sex: M
Population Size: 1
Sources: Page: p. 30
Nausea moderate, 1 patient
Disc. AE
20 mg single, intravenous
Dose: 20 mg
Route: intravenous
Route: single
Dose: 20 mg
Sources: Page: p. 30
healthy, 21 yeras
n = 1
Health Status: healthy
Age Group: 21 yeras
Sex: M
Population Size: 1
Sources: Page: p. 30
Retching moderate, 1 patient
Disc. AE
20 mg single, intravenous
Dose: 20 mg
Route: intravenous
Route: single
Dose: 20 mg
Sources: Page: p. 30
healthy, 21 yeras
n = 1
Health Status: healthy
Age Group: 21 yeras
Sex: M
Population Size: 1
Sources: Page: p. 30
Dizziness 1 patient
Disc. AE
300 mg single, intravenous
Highest studied dose
Dose: 300 mg
Route: intravenous
Route: single
Dose: 300 mg
Sources: Page: p. 30
healthy, 23 years
n = 1
Health Status: healthy
Age Group: 23 years
Sex: M
Population Size: 1
Sources: Page: p. 30
Back pain mild, 1 patient
Disc. AE
300 mg single, intravenous
Highest studied dose
Dose: 300 mg
Route: intravenous
Route: single
Dose: 300 mg
Sources: Page: p. 30
healthy, 23 years
n = 1
Health Status: healthy
Age Group: 23 years
Sex: M
Population Size: 1
Sources: Page: p. 30
Abdominal discomfort mild, 1 patient
Disc. AE
200 mg single, intravenous
Dose: 200 mg
Route: intravenous
Route: single
Dose: 200 mg
Sources: Page: p. 30
healthy, 54 yeras
n = 1
Health Status: healthy
Age Group: 54 yeras
Sex: M
Population Size: 1
Sources: Page: p. 30
Diarrhea mild, 1 patient
Disc. AE
200 mg single, intravenous
Dose: 200 mg
Route: intravenous
Route: single
Dose: 200 mg
Sources: Page: p. 30
healthy, 54 yeras
n = 1
Health Status: healthy
Age Group: 54 yeras
Sex: M
Population Size: 1
Sources: Page: p. 30
Dizziness mild, 1 patient
Disc. AE
200 mg single, intravenous
Dose: 200 mg
Route: intravenous
Route: single
Dose: 200 mg
Sources: Page: p. 30
healthy, 54 yeras
n = 1
Health Status: healthy
Age Group: 54 yeras
Sex: M
Population Size: 1
Sources: Page: p. 30
Dry mouth mild, 1 patient
Disc. AE
200 mg single, intravenous
Dose: 200 mg
Route: intravenous
Route: single
Dose: 200 mg
Sources: Page: p. 30
healthy, 54 yeras
n = 1
Health Status: healthy
Age Group: 54 yeras
Sex: M
Population Size: 1
Sources: Page: p. 30
Feeling hot mild, 1 patient
Disc. AE
200 mg single, intravenous
Dose: 200 mg
Route: intravenous
Route: single
Dose: 200 mg
Sources: Page: p. 30
healthy, 54 yeras
n = 1
Health Status: healthy
Age Group: 54 yeras
Sex: M
Population Size: 1
Sources: Page: p. 30
Headache mild, 1 patient
Disc. AE
200 mg single, intravenous
Dose: 200 mg
Route: intravenous
Route: single
Dose: 200 mg
Sources: Page: p. 30
healthy, 54 yeras
n = 1
Health Status: healthy
Age Group: 54 yeras
Sex: M
Population Size: 1
Sources: Page: p. 30
Presyncope mild, 1 patient
Disc. AE
200 mg single, intravenous
Dose: 200 mg
Route: intravenous
Route: single
Dose: 200 mg
Sources: Page: p. 30
healthy, 54 yeras
n = 1
Health Status: healthy
Age Group: 54 yeras
Sex: M
Population Size: 1
Sources: Page: p. 30
OverviewDrug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
no [IC50 >100 uM]
no [IC50 >100 uM]
no
no
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.
Page: 6.0
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.
Page: 31.0
yes [IC50 22 uM]
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.
Page: 31.0
yes [IC50 41 uM]
yes [IC50 49 uM]
yes [IC50 8.65 uM]
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.
Page: 31.0
yes [IC50 9.6 uM]
yes [Ki 3.4 uM]
yes
yes
yes
yes
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.
Page: 6.0
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
no
no
no
yes
yes
yes
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.
Page: 6.0
Tox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
PubMed

PubMed

TitleDatePubMed
Management of postoperative nausea and vomiting: focus on palonosetron.
2009 Feb
Rolapitant for the prevention of postoperative nausea and vomiting: a prospective, double-blinded, placebo-controlled randomized trial.
2011 Apr
Patents

Sample Use Guides

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 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 Sat Jun 26 13:31:17 UTC 2021
Edited
by admin
on Sat Jun 26 13:31:17 UTC 2021
Record UNII
NLE429IZUC
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
ROLAPITANT
DASH   INN   USAN   WHO-DD  
INN   USAN  
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
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
ROLAPITANT [WHO-DD]
Common Name English
Classification Tree Code System Code
NDF-RT N0000175786
Created by admin on Sat Jun 26 13:31:17 UTC 2021 , Edited by admin on Sat Jun 26 13:31:17 UTC 2021
WHO-ATC A04AD14
Created by admin on Sat Jun 26 13:31:17 UTC 2021 , Edited by admin on Sat Jun 26 13:31:17 UTC 2021
NCI_THESAURUS C267
Created by admin on Sat Jun 26 13:31:17 UTC 2021 , Edited by admin on Sat Jun 26 13:31:17 UTC 2021
Code System Code Type Description
NDF-RT
N0000182137
Created by admin on Sat Jun 26 13:31:17 UTC 2021 , Edited by admin on Sat Jun 26 13:31:17 UTC 2021
PRIMARY Cytochrome P450 2D6 Inhibitors [MoA]
MERCK INDEX
M11844
Created by admin on Sat Jun 26 13:31:17 UTC 2021 , Edited by admin on Sat Jun 26 13:31:17 UTC 2021
PRIMARY
NCI_THESAURUS
C97952
Created by admin on Sat Jun 26 13:31:17 UTC 2021 , Edited by admin on Sat Jun 26 13:31:17 UTC 2021
PRIMARY
ChEMBL
CHEMBL3707331
Created by admin on Sat Jun 26 13:31:17 UTC 2021 , Edited by admin on Sat Jun 26 13:31:17 UTC 2021
PRIMARY
EPA CompTox
552292-08-7
Created by admin on Sat Jun 26 13:31:17 UTC 2021 , Edited by admin on Sat Jun 26 13:31:17 UTC 2021
PRIMARY
DRUG BANK
DB09291
Created by admin on Sat Jun 26 13:31:17 UTC 2021 , Edited by admin on Sat Jun 26 13:31:17 UTC 2021
PRIMARY
FDA UNII
NLE429IZUC
Created by admin on Sat Jun 26 13:31:17 UTC 2021 , Edited by admin on Sat Jun 26 13:31:17 UTC 2021
PRIMARY
INN
8882
Created by admin on Sat Jun 26 13:31:17 UTC 2021 , Edited by admin on Sat Jun 26 13:31:17 UTC 2021
PRIMARY
PUBCHEM
10311306
Created by admin on Sat Jun 26 13:31:17 UTC 2021 , Edited by admin on Sat Jun 26 13:31:17 UTC 2021
PRIMARY
DRUG CENTRAL
5027
Created by admin on Sat Jun 26 13:31:17 UTC 2021 , Edited by admin on Sat Jun 26 13:31:17 UTC 2021
PRIMARY
RXCUI
1665496
Created by admin on Sat Jun 26 13:31:17 UTC 2021 , Edited by admin on Sat Jun 26 13:31:17 UTC 2021
PRIMARY RxNorm
EVMPD
SUB121121
Created by admin on Sat Jun 26 13:31:17 UTC 2021 , Edited by admin on Sat Jun 26 13:31:17 UTC 2021
PRIMARY
CAS
552292-08-7
Created by admin on Sat Jun 26 13:31:17 UTC 2021 , Edited by admin on Sat Jun 26 13:31:17 UTC 2021
PRIMARY
IUPHAR
5749
Created by admin on Sat Jun 26 13:31:17 UTC 2021 , Edited by admin on Sat Jun 26 13:31:17 UTC 2021
PRIMARY
NDF-RT
N0000190113
Created by admin on Sat Jun 26 13:31:17 UTC 2021 , Edited by admin on Sat Jun 26 13:31:17 UTC 2021
PRIMARY Breast Cancer Resistance Protein Inhibitors [MoA]
WIKIPEDIA
Rolapitant
Created by admin on Sat Jun 26 13:31:17 UTC 2021 , Edited by admin on Sat Jun 26 13:31:17 UTC 2021
PRIMARY
NDF-RT
N0000185503
Created by admin on Sat Jun 26 13:31:17 UTC 2021 , Edited by admin on Sat Jun 26 13:31:17 UTC 2021
PRIMARY P-Glycoprotein Inhibitors [MoA]
Related Record Type Details
METABOLIC ENZYME -> SUBSTRATE
MAJOR
TARGET -> INHIBITOR
ANTAGONIST
Ki
EXCRETED UNCHANGED->SUBSTANCE
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
MAJOR
FECAL
SALT/SOLVATE -> PARENT
SALT/SOLVATE -> PARENT
BINDER->LIGAND
BINDING
TRANSPORTER -> NON-SUBSTRATE
METABOLIC ENZYME -> INHIBITOR
COMPETITIVE INHIBITOR
Ki
TRANSPORTER -> INHIBITOR
[I]/IC50 value for p-gp inhibition was estimated to be 0.23. Based on [I]/IC50 > 0.1 a potential in-vivo drug interaction via inhibition of p-gp cannot be ruled out.
INHIBITOR
IC50
Related Record Type Details
METABOLITE ACTIVE -> PARENT
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.
MAJOR
PLASMA
Related Record Type Details
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
Biological Half-life PHARMACOKINETIC
Volume of Distribution PHARMACOKINETIC