PALONOSETRON

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C19H24N2O
Molecular Weight	296.4067
Optical Activity	( - )
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[H][C@]12CCCC3=C1C(=CC=C3)C(=O)N(C2)[C@@H]4CN5CCC4CC5

InChI

InChIKey=CPZBLNMUGSZIPR-NVXWUHKLSA-N

InChI=1S/C19H24N2O/c22-19-16-6-2-4-14-3-1-5-15(18(14)16)11-21(19)17-12-20-9-7-13(17)8-10-20/h2,4,6,13,15,17H,1,3,5,7-12H2/t15-,17-/m1/s1

HIDE SMILES / InChI

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021372s020lbl.pdf

Palonosetron (INN, trade name Aloxi) is a 5-HT3 antagonist used in the prevention and treatment of postoperative and chemotherapy-induced nausea and vomiting (PONV and CINV). Palonosetron is a 5-HT3 receptor antagonist with a strong binding affinity for this receptor and little or no affinity for other receptors. Cancer chemotherapy may be associated with a high incidence of nausea and vomiting, particularly when certain agents, such as cisplatin, are used. 5-HT3 receptors are located on the nerve terminals of the vagus in the periphery and centrally in the chemoreceptor trigger zone of the area postrema. It is thought that chemotherapeutic agents produce nausea and vomiting by releasing serotonin from the enterochromaffin cells of the small intestine and that the released serotonin then activates 5-HT3 receptors located on vagal afferents to initiate the vomiting reflex. Postoperative nausea and vomiting is influenced by multiple patients, surgical and anesthesia-related factors and is triggered by the release of 5-HT in a cascade of neuronal events involving both the central nervous system and the gastrointestinal tract. The 5-HT3 receptor has been demonstrated to selectively participate in the emetic response. The most common adverse effects are a headache, which occurs in 4–11% of patients, and constipation in up to 6% of patients. In less than 1% of patients, other gastrointestinal disorders occur, as well as sleeplessness, first- and second-degree atrioventricular block, muscle pain and shortness of breath. Palonosetron is similarly well tolerated as other sections, and slightly less than placebo.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Serotonin 3a (5-HT3a) receptor 46 Target ID: CHEMBL1899 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24128813	Antagonist 2778		0.83 nM [IC50]
Serotonin 3 (5-HT3) receptor 59 Target ID: CHEMBL2111332 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24128813	Antagonist 2778		0.83 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Postoperative nausea and vomiting 29 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021372s020lbl.pdf	Primary		Approved 8429	ALOXI Approved Use ALOXI is a serotonin-3 (5-HT3) receptor antagonist indicated in adults for: Moderately emetogenic cancer chemotherapy --prevention of acute and delayed nausea and vomiting associated with initial and repeat courses (1.1) Highly emetogenic cancer chemotherapy -- prevention of acute nausea and vomiting associated with initial and repeat courses (1.1) Prevention of postoperative nausea and vomiting (PONV) for up to 24 hours following surgery. Efficacy beyond 24 hours has not been demonstrated (1.3) ALOXI is indicated in pediatric patients aged 1 month to less than 17 years for: Prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy (1.2) 1.1 Chemotherapy-Induced Nausea and Vomiting in Adults ALOXI is indicated for: Moderately emetogenic cancer chemotherapy --prevention of acute and delayed nausea and vomiting associated with initial and repeat courses Highly emetogenic cancer chemotherapy -- prevention of acute nausea and vomiting associated with initial and repeat courses 1.2 Chemotherapy-Induced Nausea and Vomiting in Pediatric Patients Aged 1 Month to Less than 17 Years ALOXI is indicated for prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy. 1.3 Postoperative Nausea and Vomiting in Adults ALOXI is indicated for prevention of postoperative nausea and vomiting (PONV) for up to 24 hours following surgery. Efficacy beyond 24 hours has not been demonstrated. As with other antiemetics, routine prophylaxis is not recommended in patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. In patients where nausea and vomiting must be avoided during the postoperative period, ALOXI is recommended even where the incidence of postoperative nausea and/or vomiting is low. Launch Date 2003
Chemotherapy induced nausea and vomiting 10 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021372s020lbl.pdf	Secondary		Approved 8429	ALOXI Approved Use ALOXI is a serotonin-3 (5-HT3) receptor antagonist indicated in adults for: Moderately emetogenic cancer chemotherapy --prevention of acute and delayed nausea and vomiting associated with initial and repeat courses (1.1) Highly emetogenic cancer chemotherapy -- prevention of acute nausea and vomiting associated with initial and repeat courses (1.1) Prevention of postoperative nausea and vomiting (PONV) for up to 24 hours following surgery. Efficacy beyond 24 hours has not been demonstrated (1.3) ALOXI is indicated in pediatric patients aged 1 month to less than 17 years for: Prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy (1.2) 1.1 Chemotherapy-Induced Nausea and Vomiting in Adults ALOXI is indicated for: Moderately emetogenic cancer chemotherapy --prevention of acute and delayed nausea and vomiting associated with initial and repeat courses Highly emetogenic cancer chemotherapy -- prevention of acute nausea and vomiting associated with initial and repeat courses 1.2 Chemotherapy-Induced Nausea and Vomiting in Pediatric Patients Aged 1 Month to Less than 17 Years ALOXI is indicated for prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy. 1.3 Postoperative Nausea and Vomiting in Adults ALOXI is indicated for prevention of postoperative nausea and vomiting (PONV) for up to 24 hours following surgery. Efficacy beyond 24 hours has not been demonstrated. As with other antiemetics, routine prophylaxis is not recommended in patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. In patients where nausea and vomiting must be avoided during the postoperative period, ALOXI is recommended even where the incidence of postoperative nausea and/or vomiting is low. Launch Date 2003

C_max

Value	Dose	Co-administered	Analyte	Population
5630 ng/L DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021372s018s019lbl.pdf	3 μg/kg bw 1 times / day multiple, intravenous dose: 3 μg/kg bw route of administration: Intravenous experiment type: MULTIPLE co-administered:		PALONOSETRON plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
35.8 μg × h/L DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021372s018s019lbl.pdf	3 μg/kg bw 1 times / day multiple, intravenous dose: 3 μg/kg bw route of administration: Intravenous experiment type: MULTIPLE co-administered:		PALONOSETRON plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
40 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021372s018s019lbl.pdf	unknown, unknown		PALONOSETRON plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
38% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021372s018s019lbl.pdf	3 μg/kg bw 1 times / day multiple, intravenous dose: 3 μg/kg bw route of administration: Intravenous experiment type: MULTIPLE co-administered:		PALONOSETRON plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
0.75 mg single, intravenous (max) Recommended Dose: 0.75 mg Route: intravenous Route: single Dose: 0.75 mg Co-administed with:: (chemotherapy) Sources: https://pubmed.ncbi.nlm.nih.gov/15139789/	unhealthy, adult n = 667 Health Status: unhealthy Condition: HIV-1 Age Group: adult Sex: unknown Population Size: 667 Sources: https://pubmed.ncbi.nlm.nih.gov/15139789/	Disc. AE: Headache... AEs leading to discontinuation/dose reduction: Headache (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/15139789/

AEs

AE	Significance	Dose	Population
Headache	1 patient Disc. AE	0.75 mg single, intravenous (max) Recommended Dose: 0.75 mg Route: intravenous Route: single Dose: 0.75 mg Co-administed with:: (chemotherapy) Sources: https://pubmed.ncbi.nlm.nih.gov/15139789/	unhealthy, adult n = 667 Health Status: unhealthy Condition: HIV-1 Age Group: adult Sex: unknown Population Size: 667 Sources: https://pubmed.ncbi.nlm.nih.gov/15139789/

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737	inhibitor 1767	substrate 1217 inhibitor 1852 inducer 97	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2A6 707 CYP2B6 810 CYP2E1 882 CYP3A 214	CYP1A2 1054	CYP1A2 701 CYP3A 129

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-372_Alox_BioPharmr.pdf#page=6 Page: 6.0	no
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-372_Alox_BioPharmr.pdf#page=6 Page: 6.0	no
CYP2A6 739	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-372_Alox_BioPharmr.pdf#page=6 Page: 6.0	no
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-372_Alox_BioPharmr.pdf#page=6 Page: 6.0	no
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-372_Alox_BioPharmr.pdf#page=6 Page: 6.0	no
CYP2D6 1891	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-372_Alox_BioPharmr.pdf#page=6 Page: 6.0	no
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-372_Alox_BioPharmr.pdf#page=6 Page: 6.0	no
CYP2E1 970	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-372_Alox_BioPharmr.pdf#page=6 Page: 6.0	no
CYP3A 298	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-372_Alox_BioPharmr.pdf#page=6 Page: 6.0	no
CYP3A 298	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-372_Alox_BioPharmr.pdf#page=6 Page: 6.0	no

Drug as victim

Target	Modality	Activity
CYP2D6 1217	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-372_Alox_BioPharmr.pdf#page=5 Page: 5.0	major
CYP1A2 1054	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-372_Alox_BioPharmr.pdf#page=5 Page: 5.0	minor
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-372_Alox_BioPharmr.pdf#page=5 Page: 5.0	minor

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-372_Alox_Pharmr_P1.pdf#page=35 Page: 35.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:85161	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:85161
ChemicalBook	CB32131051	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB32131051
ChemicalBook	CB7257940	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB7257940
MolPort	MolPort-005-941-486	https://www.molport.com/shop/molecule-link/MolPort-005-941-486
MolPort	MolPort-020-005-893	https://www.molport.com/shop/molecule-link/MolPort-020-005-893
ZINC	ZINC000003795819	http://zinc15.docking.org/substances/ZINC000003795819

PubMed

Title	Date	PubMed
Palonosetron (Aloxi): a second-generation 5-HT₃ receptor antagonist for chemotherapy-induced nausea and vomiting.	2006 Oct	17106506
Computational analysis of ligand recognition sites of homo- and heteropentameric 5-HT3 receptors.	2010 Nov	20724042

Patents

Sample Use Guides

In Vivo Use Guide

Adults 0.25 mg x 1 Infuse over 30 seconds beginning approx. 30 min before the start of chemotherapy. Pediatrics (1 month to less than 17 years) 20 micrograms per kilogram (max 1.5 mg) x 1 Infuse over 15 minutes beginning approx. 30 min before the start of chemotherapy

Route of Administration: Intravenous

In Vitro Use Guide

NG108-15 cells, known to express both 5-HT3 and NK-1 receptors, were grown in high-glucose Dulbecco’s modified Eagle’s medium supplemented with a mixture of sodium hypoxanthine, aminopterin, and thymidine, 10% heat-inactivated fetal bovine serum, and 2 mM glutamine to 90% confluence. Cells were incubated with palonosetron (10 nM), granisetron (60 nM), and ondansetron (300 nM) for 2 h. Antagonist concentrations were approximately 50-fold Kd in each case to make sure receptors were saturated. Subsequently, antagonists were removed and cells were incubated with growth media without antagonist for an additional hour to allow for dissociation of antagonists still bound to the cell. Next, cell media were replaced with isosmotic HEPES buffer (20 mM, pH 7.4, 130 mM NaCl, 2 mM KCl, 1 mM MgCl2, and 2 mM CaCl2) containing 2 M Fluo-4 acetoxymethyl (AM) ester and pluronic acid (0.04%). Pluronic acid was added as nonionic surfactant to sequester the AM ester molecules into micelles for cell uptake. Cells were incubated for 1 h to allow for cell uptake of the AM ester. Cells were then incubated with SP at various concentrations for 1 h in HEPES buffer without the AM ester and pluronic acid. Subsequently, measurement of calcium-ion release caused by SP alone or SP plus serotonin (107 M final concentration added immediately before measurement) was made by using a fluorometric imaging plate reader.

Name

Type

Language

PALONOSETRON

Official Name

English

NSC-743769

Code

English

PALONOSETRON, (3AS, 3S)-

Common Name

English

Palonosetron [WHO-DD]

Common Name

English

PALONOSETRON [VANDF]

Common Name

English

PALONOSETRON [MI]

Common Name

English

palonosetron [INN]

Common Name

English

1H-BENZ(DE)ISOQUINOLIN-1-ONE, 2-(3S)-1-AZABICYCLO(2.2.2)OCT-3-YL-2,3,3A,4,5,6-HEXAHYDRO-, (3AS)-

Systematic Name

English

(-)-PALONOSETRON

Common Name

English

Classification Tree Code System Code

EMA ASSESSMENT REPORTS

PALONOSETRON ACCORD (AUTHORIZED: CANCER, NAUSEA, VOMITING)