TREPROSTINIL SODIUM

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C23H33O5.Na
Molecular Weight	412.4949
Optical Activity	UNSPECIFIED
Defined Stereocenters	5 / 5
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[Na+].[H][C@]12C[C@@H](O)[C@H](CC[C@@H](O)CCCCC)[C@@]1([H])CC3=C(C2)C(OCC([O-])=O)=CC=C3

InChI

InChIKey=IQKAWAUTOKVMLE-ZSESPEEFSA-M

InChI=1S/C23H34O5.Na/c1-2-3-4-7-17(24)9-10-18-19-11-15-6-5-8-22(28-14-23(26)27)20(15)12-16(19)13-21(18)25;/h5-6,8,16-19,21,24-25H,2-4,7,9-14H2,1H3,(H,26,27);/q;+1/p-1/t16-,17-,18+,19-,21+;/m0./s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/?term=27286723
Curator's Comment: Description was created based on several sources, including: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3412595/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515411/

Treprostinil (marketed under the trade names Remodulin for infusion) is a vasodilator that is used for the treatment of pulmonary arterial hypertension. Pulmonary arterial hypertension (PAH) is a disease in which blood pressure is abnormally high in the arteries between the heart and lungs. PAH is characterized by symptoms of shortness of breath during physical exertion. The condition can ultimately lead to heart failure. Treprostinil is a potent oral antiplatelet agent. The major pharmacologic actions of treprostinil are direct vasodilation of pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation. In animals, the vasodilatory effects reduce right and left ventricular afterload and increase cardiac output and stroke volume. Other studies have shown that treprostinil causes a dose-related negative inotropic and lusitropic effect. No major effects on cardiac conduction have been observed. Treprostinil had high affinity for the Prostaglandin D2 receptor (DP1), Prostaglandin E2 receptor EP2 subtype (EP2) and Prostaglandin D2 receptor (IP) receptors (Ki 4.4, 3.6 and 32 nM, respectively), low affinity for EP1 and EP4 receptors and even lower affinity for EP3, Prostaglandin F (FP) and thromboxane (TP) receptors. Treprostinil has demonstrated a unique effect on PPAR gamma, a transcription factor important in vascular pathogenesis as a mediator of proliferation, inflammation and apoptosis. Through a complementary, yet cyclic AMP-independent pathway, treprostinil activates PPARs, another mechanism that contributes to the anti-growth benefits of the prostacyclin class.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Prostanoid IP receptor 18 Target ID: CHEMBL1995 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18574748	Agonist 2678	32.0 nM [Ki]
Prostanoid DP receptor 15 Target ID: CHEMBL4427 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22480736	Agonist 2678	4.4 nM [Ki]
Prostanoid EP2 receptor 19 Target ID: CHEMBL1881 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22480736	Agonist 2678	3.6 nM [Ki]
Peroxisome proliferator-activated receptor delta 29 Target ID: CHEMBL3979 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16239641	Agonist 2678

Conditions

Condition	Modality	Targets	Highest Phase	Product
Pulmonary arterial hypertension 35 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021272s009lbl.pdf	Primary		Approved 8429	REMODULIN Approved Use Remodulin is a prostacyclin vasodilator indicated for: Treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to diminish symptoms associated with exercise. Studies establishing effectiveness included patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (58%), PAH associated with congenital systemic-to-pulmonary shunts (23%), or PAH associated with connective tissue diseases (19%) (1.1) Patients who require transition from Flolan®, to reduce the rate of clinical deterioration. The risks and benefits of each drug should be carefully considered prior to transition. (1.2) 1.1 Pulmonary Arterial Hypertension Remodulin is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to diminish symptoms associated with exercise. Studies establishing effectiveness included patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (58%), PAH associated with congenital systemic-to-pulmonary shunts (23%), or PAH associated with connective tissue diseases (19%) [see Clinical Studies (14.1) Launch Date 2002

C_max

Value	Dose	Co-administered	Analyte	Population
0.71 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24603117	0.5 mg 3 times / day multiple, oral dose: 0.5 mg route of administration: Oral experiment type: MULTIPLE co-administered:		TREPROSTINIL plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
0.54 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24603117	0.5 mg single, oral dose: 0.5 mg route of administration: Oral experiment type: SINGLE co-administered:		TREPROSTINIL plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED

AUC

Value	Dose	Co-administered	Analyte	Population
6.53 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24603117	0.5 mg 3 times / day multiple, oral dose: 0.5 mg route of administration: Oral experiment type: MULTIPLE co-administered:		TREPROSTINIL plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
2.46 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24603117	0.5 mg single, oral dose: 0.5 mg route of administration: Oral experiment type: SINGLE co-administered:		TREPROSTINIL plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED

T_1/2

Value	Dose	Co-administered	Analyte	Population
1.34 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24603117	0.5 mg 3 times / day multiple, oral dose: 0.5 mg route of administration: Oral experiment type: MULTIPLE co-administered:		TREPROSTINIL plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
1.06 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24603117	0.5 mg single, oral dose: 0.5 mg route of administration: Oral experiment type: SINGLE co-administered:		TREPROSTINIL plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED

F_unbound

Value	Dose	Co-administered	Analyte	Population
9% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021272s020lbledt.pdf			TREPROSTINIL plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
20 mg 3 times / day steady, subcutaneous Overdose Dose: 20 mg, 3 times / day Route: subcutaneous Route: steady Dose: 20 mg, 3 times / day Co-administed with:: chlorothiazide(500 mg) lasix(40 mg) coumadin(4 mg) Sources: https://pubmed.ncbi.nlm.nih.gov/19285625/	unhealthy, 10 years n = 1 Health Status: unhealthy Condition: pulmonary hypertension Age Group: 10 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/19285625/	Disc. AE: Nausea, Blurred vision... AEs leading to discontinuation/dose reduction: Nausea (1 patient) Blurred vision (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/19285625/
7.5 mg single, subcutaneous Overdose Dose: 7.5 mg Route: subcutaneous Route: single Dose: 7.5 mg Sources: https://pubmed.ncbi.nlm.nih.gov/29674328/	unhealthy, 29 years n = 1 Health Status: unhealthy Condition: group 1 pulmonary arterial hypertension Age Group: 29 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/29674328/	Disc. AE: Circulatory collapse... AEs leading to discontinuation/dose reduction: Circulatory collapse (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/29674328/
150 ug single, respiratory Highest studied dose Dose: 150 ug Route: respiratory Route: single Dose: 150 ug Sources: https://pubmed.ncbi.nlm.nih.gov/33282202/	healthy, 30.3 years n = 43 Health Status: healthy Age Group: 30.3 years Sex: M+F Population Size: 43 Sources: https://pubmed.ncbi.nlm.nih.gov/33282202/	Other AEs: Cough, Throat irritation... Other AEs: Cough (26 patients) Throat irritation (26 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/33282202/
100 mg single, subcutaneous (min) Overdose Dose: 100 mg Route: subcutaneous Route: single Dose: 100 mg Sources: https://pubmed.ncbi.nlm.nih.gov/23662045/	unhealthy, 58 years n = 1 Health Status: unhealthy Condition: CREST syndrome, Raynaud's syndrome, esophageal motility impairment, and severe pulmonary hypertension Age Group: 58 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/23662045/	Disc. AE: Hypotension, Tachycardia... AEs leading to discontinuation/dose reduction: Hypotension (1 patient) Tachycardia (1 patient) Arrhythmia ventricular (1 patient) Dyspnea (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/23662045/
36 ug 4 times / day steady, respiratory (max) Recommended Dose: 36 ug, 4 times / day Route: respiratory Route: steady Dose: 36 ug, 4 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/22917554/	unhealthy, 7.1 - 19.2 years n = 29 Health Status: unhealthy Condition: pulmonary hypertension Age Group: 7.1 - 19.2 years Sex: M+F Population Size: 29 Sources: https://pubmed.ncbi.nlm.nih.gov/22917554/	Disc. AE: Bronchospasm... AEs leading to discontinuation/dose reduction: Bronchospasm (3 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/22917554/

AEs

AE	Significance	Dose	Population
Blurred vision	1 patient Disc. AE	20 mg 3 times / day steady, subcutaneous Overdose Dose: 20 mg, 3 times / day Route: subcutaneous Route: steady Dose: 20 mg, 3 times / day Co-administed with:: chlorothiazide(500 mg) lasix(40 mg) coumadin(4 mg) Sources: https://pubmed.ncbi.nlm.nih.gov/19285625/	unhealthy, 10 years n = 1 Health Status: unhealthy Condition: pulmonary hypertension Age Group: 10 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/19285625/
Nausea	1 patient Disc. AE	20 mg 3 times / day steady, subcutaneous Overdose Dose: 20 mg, 3 times / day Route: subcutaneous Route: steady Dose: 20 mg, 3 times / day Co-administed with:: chlorothiazide(500 mg) lasix(40 mg) coumadin(4 mg) Sources: https://pubmed.ncbi.nlm.nih.gov/19285625/	unhealthy, 10 years n = 1 Health Status: unhealthy Condition: pulmonary hypertension Age Group: 10 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/19285625/
Circulatory collapse	1 patient Disc. AE	7.5 mg single, subcutaneous Overdose Dose: 7.5 mg Route: subcutaneous Route: single Dose: 7.5 mg Sources: https://pubmed.ncbi.nlm.nih.gov/29674328/	unhealthy, 29 years n = 1 Health Status: unhealthy Condition: group 1 pulmonary arterial hypertension Age Group: 29 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/29674328/
Cough	26 patients	150 ug single, respiratory Highest studied dose Dose: 150 ug Route: respiratory Route: single Dose: 150 ug Sources: https://pubmed.ncbi.nlm.nih.gov/33282202/	healthy, 30.3 years n = 43 Health Status: healthy Age Group: 30.3 years Sex: M+F Population Size: 43 Sources: https://pubmed.ncbi.nlm.nih.gov/33282202/
Throat irritation	26 patients	150 ug single, respiratory Highest studied dose Dose: 150 ug Route: respiratory Route: single Dose: 150 ug Sources: https://pubmed.ncbi.nlm.nih.gov/33282202/	healthy, 30.3 years n = 43 Health Status: healthy Age Group: 30.3 years Sex: M+F Population Size: 43 Sources: https://pubmed.ncbi.nlm.nih.gov/33282202/
Arrhythmia ventricular	1 patient Disc. AE	100 mg single, subcutaneous (min) Overdose Dose: 100 mg Route: subcutaneous Route: single Dose: 100 mg Sources: https://pubmed.ncbi.nlm.nih.gov/23662045/	unhealthy, 58 years n = 1 Health Status: unhealthy Condition: CREST syndrome, Raynaud's syndrome, esophageal motility impairment, and severe pulmonary hypertension Age Group: 58 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/23662045/
Dyspnea	1 patient Disc. AE	100 mg single, subcutaneous (min) Overdose Dose: 100 mg Route: subcutaneous Route: single Dose: 100 mg Sources: https://pubmed.ncbi.nlm.nih.gov/23662045/	unhealthy, 58 years n = 1 Health Status: unhealthy Condition: CREST syndrome, Raynaud's syndrome, esophageal motility impairment, and severe pulmonary hypertension Age Group: 58 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/23662045/
Hypotension	1 patient Disc. AE	100 mg single, subcutaneous (min) Overdose Dose: 100 mg Route: subcutaneous Route: single Dose: 100 mg Sources: https://pubmed.ncbi.nlm.nih.gov/23662045/	unhealthy, 58 years n = 1 Health Status: unhealthy Condition: CREST syndrome, Raynaud's syndrome, esophageal motility impairment, and severe pulmonary hypertension Age Group: 58 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/23662045/
Tachycardia	1 patient Disc. AE	100 mg single, subcutaneous (min) Overdose Dose: 100 mg Route: subcutaneous Route: single Dose: 100 mg Sources: https://pubmed.ncbi.nlm.nih.gov/23662045/	unhealthy, 58 years n = 1 Health Status: unhealthy Condition: CREST syndrome, Raynaud's syndrome, esophageal motility impairment, and severe pulmonary hypertension Age Group: 58 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/23662045/
Bronchospasm	3 patients Disc. AE	36 ug 4 times / day steady, respiratory (max) Recommended Dose: 36 ug, 4 times / day Route: respiratory Route: steady Dose: 36 ug, 4 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/22917554/	unhealthy, 7.1 - 19.2 years n = 29 Health Status: unhealthy Condition: pulmonary hypertension Age Group: 7.1 - 19.2 years Sex: M+F Population Size: 29 Sources: https://pubmed.ncbi.nlm.nih.gov/22917554/

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inducer 781	substrate 1037 inducer 389	substrate 1217	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	CYP2C8 693 CYP1A2 1054 CYP2A6 543 CYP2C19 991 CYP4A11 119	CYP1A2 701 CYP2B6 547 CYP2C19 293

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022387s000ClinPharmR.pdf#page=13 Page: 13.0	no
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022387s000ClinPharmR.pdf#page=13 Page: 13.0	no
CYP2C19 1553	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022387s000ClinPharmR.pdf#page=13 Page: 13.0	no
CYP2C9 1819	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022387s000ClinPharmR.pdf#page=13 Page: 13.0	no
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022387s000ClinPharmR.pdf#page=13 Page: 13.0	no

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP2C8 693	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022387s000ClinPharmR.pdf#page12 Page: 12,14	major	yes (co-administration study) Comment: Treprostinil plasma AUC and Cmax increased approximately 2-fold when administered with gemfibrozil; Treprostinil AUC decreased by 30% when adminsitered with rifampin; Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022387s000ClinPharmR.pdf#page12 Page: 12,14
CYP2C9 1037	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022387s000ClinPharmR.pdf#page12 Page: 12,14	minor	weak (co-administration study) Comment: Treprostinil AUC decreased approximately 14%, no effect on Cmax when adminstered with fluconazole; Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022387s000ClinPharmR.pdf#page12 Page: 12,14
CYP1A2 1054	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022387s000ClinPharmR.pdf#page12 Page: 12.0	no
CYP2A6 543	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022387s000ClinPharmR.pdf#page12 Page: 12.0	no
CYP2C19 991	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022387s000ClinPharmR.pdf#page12 Page: 12.0	no
CYP2D6 1217	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022387s000ClinPharmR.pdf#page12 Page: 12.0	no
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022387s000ClinPharmR.pdf#page12 Page: 12.0	no
CYP4A11 119	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022387s000ClinPharmR.pdf#page12 Page: 12.0	no

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022387s000PharmR.pdf#page=7 Page: 7.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:50861	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:50861
ChemicalBook	CB32460050	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB32460050
MolPort	MolPort-027-720-928	https://www.molport.com/shop/molecule-link/MolPort-027-720-928
ZINC	ZINC000003800475	http://zinc15.docking.org/substances/ZINC000003800475

PubMed

Title	Date	PubMed
Stability and preservative effectiveness of treprostinil sodium after dilution in common intravenous diluents.	2003 May 1	12756943
Gateways to clinical trials.	2003 Sep	14571286
Absolute bioavailability and pharmacokinetics of treprostinil sodium administered by acute subcutaneous infusion.	2004 Jan	14681345
Gateways to clinical trials.	2004 Jun	15319815
Overview of treprostinil sodium for the treatment of pulmonary arterial hypertension.	2004 Mar	15148531
Gateways to clinical trials.	2004 Mar	15071612
Gateways to clinical trials.	2005 Dec	16395422
Gateways to clinical trials.	2005 Sep	16258596
Role of prostacyclin versus peroxisome proliferator-activated receptor beta receptors in prostacyclin sensing by lung fibroblasts.	2006 Feb	16239641
[The best of clinical cardiovascular pharmacology in 2005].	2006 Jan	16479971
Gateways to clinical trials.	2006 Jan-Feb	16541195
The prostacyclin analog, treprostinil sodium, provides symptom relief in severe Buerger's disease--a case report and review of literature.	2006 Jan-Feb	16444463
Gateways to clinical trials.	2006 Jul-Aug	16894408
Efficacy of long-term subcutaneous treprostinil sodium therapy in pulmonary hypertension.	2006 Jun	16778286
Gateways to clinical trials.	2006 Mar	16636723
Gateways to clinical trials.	2006 Sep	17003851
Gateways to clinical trials.	2007 Nov	18193114
Patient safety challenges in treprostinil therapy.	2008 Apr	18517170
Treatment of a nonhealing saphenous vein harvest graft with treprostinil sodium.	2008 Apr	18355483
Dose proportionality of treprostinil sodium administered by continuous subcutaneous and intravenous infusion.	2008 Jan	18094217
A novel catheter system for totally implantable intravenous drug therapy: assessment of catheter function and patency with trepostinil therapy.	2008 Jan-Mar	18379976
Primary pulmonary hypertension as a manifestation of adult multi-system mitochondrial disorder.	2009 Apr 30	19430571
Inhaled treprostinil and pulmonary arterial hypertension.	2010 Dec 3	21191432

Patents

Sample Use Guides

In Vivo Use Guide

1.25 ng/kg/min (initial dose for continuous infusion, dosage should be chronically adjusted depending on clinical response)

Route of Administration: Other

In Vitro Use Guide

Treprostinil (0.15 - 15 ng/ml) rat cardiomyocytes

Name

Type

Language

TREPROSTINIL SODIUM

Common Name

English

TREPROSTINIL SODIUM SALT

Common Name

English

ACETIC ACID, 2-(((1R,2R,3AS,9AS)-2,3,3A,4,9,9A-HEXAHYDRO-2-HYDROXY-1-((3S)-3-HYDROXYOCTYL)-1H-BENZ(F)INDEN-5-YL)OXY)-, SODIUM SALT (1:1)

Common Name

English

TREPROSTINIL SODIUM [ORANGE BOOK]

Common Name

English

TREPROSTINIL SODIUM SALT [MI]

Common Name

English

ACETIC ACID, (((1R,2R,3AS,9AS)-2,3,3A,4,9,9A-HEXAHYDRO-2-HYDROXY-1-((3S)-3-HYDROXYOCTYL)-1H-BENZ(F)INDEN-5-YL)OXY)-, MONOSODIUM SALT

Common Name

English

TREPROSTINIL SODIUM [MART.]

Common Name

English

Treprostinil sodium [WHO-DD]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C78568