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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 of TREPROSTINIL SODIUM

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

Molecular Formula C23H33O5
Molecular Weight 389.5051
Charge -1
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 5 / 5
E/Z Centers 0
Optical Activity UNSPECIFIED

Molecular Formula Na
Molecular Weight 22.9898
Charge 1
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Description
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

Curator's Comment: By 1976, Vane and fellow researcher Salvador Moncada published the first paper on prostacyclin, in the scientific journal Nature. The collaboration produced a synthetic molecule which was given the name epoprostenol. But like native prostacyclin, the structure of the epoprostenol molecule proved to be unstable in solution, prone to rapid degradation. This presented a challenge for both in vitro experiments and clinical applications. To overcome this challenge, the research team that discovered prostacyclin was determined to continue the research in an attempt to build upon the success they had seen with the prototype molecule. The research team synthesized nearly 1,000 analogs.

Approval Year

TargetsConditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
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
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
0.71 ng/mL
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
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

AUC

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

T1/2

ValueDoseCo-administeredAnalytePopulation
1.34 h
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
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
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
9%
TREPROSTINIL plasma
Homo sapiens
population: UNKNOWN
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse 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:
unhealthy, 10 years
n = 1
Health Status: unhealthy
Condition: pulmonary hypertension
Age Group: 10 years
Sex: F
Population Size: 1
Sources:
Disc. AE: Nausea, Blurred vision...
AEs leading to
discontinuation/dose reduction:
Nausea (1 patient)
Blurred vision (1 patient)
Sources:
7.5 mg single, subcutaneous
Overdose
Dose: 7.5 mg
Route: subcutaneous
Route: single
Dose: 7.5 mg
Sources:
unhealthy, 29 years
n = 1
Health Status: unhealthy
Condition: group 1 pulmonary arterial hypertension
Age Group: 29 years
Sex: F
Population Size: 1
Sources:
Disc. AE: Circulatory collapse...
AEs leading to
discontinuation/dose reduction:
Circulatory collapse (1 patient)
Sources:
150 ug single, respiratory
Highest studied dose
Dose: 150 ug
Route: respiratory
Route: single
Dose: 150 ug
Sources:
healthy, 30.3 years
n = 43
Health Status: healthy
Age Group: 30.3 years
Sex: M+F
Population Size: 43
Sources:
Other AEs: Cough, Throat irritation...
Other AEs:
Cough (26 patients)
Throat irritation (26 patients)
Sources:
100 mg single, subcutaneous (min)
Overdose
Dose: 100 mg
Route: subcutaneous
Route: single
Dose: 100 mg
Sources:
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:
Disc. AE: Hypotension, Tachycardia...
AEs leading to
discontinuation/dose reduction:
Hypotension (1 patient)
Tachycardia (1 patient)
Arrhythmia ventricular (1 patient)
Dyspnea (1 patient)
Sources:
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:
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:
Disc. AE: Bronchospasm...
AEs leading to
discontinuation/dose reduction:
Bronchospasm (3 patients)
Sources:
AEs

AEs

AESignificanceDosePopulation
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:
unhealthy, 10 years
n = 1
Health Status: unhealthy
Condition: pulmonary hypertension
Age Group: 10 years
Sex: F
Population Size: 1
Sources:
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:
unhealthy, 10 years
n = 1
Health Status: unhealthy
Condition: pulmonary hypertension
Age Group: 10 years
Sex: F
Population Size: 1
Sources:
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:
unhealthy, 29 years
n = 1
Health Status: unhealthy
Condition: group 1 pulmonary arterial hypertension
Age Group: 29 years
Sex: F
Population Size: 1
Sources:
Cough 26 patients
150 ug single, respiratory
Highest studied dose
Dose: 150 ug
Route: respiratory
Route: single
Dose: 150 ug
Sources:
healthy, 30.3 years
n = 43
Health Status: healthy
Age Group: 30.3 years
Sex: M+F
Population Size: 43
Sources:
Throat irritation 26 patients
150 ug single, respiratory
Highest studied dose
Dose: 150 ug
Route: respiratory
Route: single
Dose: 150 ug
Sources:
healthy, 30.3 years
n = 43
Health Status: healthy
Age Group: 30.3 years
Sex: M+F
Population Size: 43
Sources:
Arrhythmia ventricular 1 patient
Disc. AE
100 mg single, subcutaneous (min)
Overdose
Dose: 100 mg
Route: subcutaneous
Route: single
Dose: 100 mg
Sources:
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:
Dyspnea 1 patient
Disc. AE
100 mg single, subcutaneous (min)
Overdose
Dose: 100 mg
Route: subcutaneous
Route: single
Dose: 100 mg
Sources:
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:
Hypotension 1 patient
Disc. AE
100 mg single, subcutaneous (min)
Overdose
Dose: 100 mg
Route: subcutaneous
Route: single
Dose: 100 mg
Sources:
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:
Tachycardia 1 patient
Disc. AE
100 mg single, subcutaneous (min)
Overdose
Dose: 100 mg
Route: subcutaneous
Route: single
Dose: 100 mg
Sources:
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:
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:
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:
Overview

OverviewOther

Drug as perpetrator​Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
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;
Page: 12,14
minor
weak (co-administration study)
Comment: Treprostinil AUC decreased approximately 14%, no effect on Cmax when adminstered with fluconazole;
Page: 12,14
no
no
no
no
no
no
Tox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
PubMed

PubMed

TitleDatePubMed
Pharmacokinetics and steady-state bioequivalence of treprostinil sodium (Remodulin) administered by the intravenous and subcutaneous route to normal volunteers.
2004 Aug
Absolute bioavailability and pharmacokinetics of treprostinil sodium administered by acute subcutaneous infusion.
2004 Jan
Gateways to clinical trials.
2004 Jul-Aug
Gateways to clinical trials.
2004 Jun
Gateways to clinical trials.
2005 Dec
Gateways to clinical trials.
2005 Jun
The prostacyclin analog, treprostinil sodium, provides symptom relief in severe Buerger's disease--a case report and review of literature.
2006 Jan-Feb
Treprostinil sodium (Remodulin), a prostacyclin analog, in the treatment of critical limb ischemia: open-label study.
2006 May-Jun
Gateways to clinical trials.
2006 Sep
The role of peroxisome proliferator-activated receptors in pulmonary vascular disease.
2007
Bloodstream infections among patients treated with intravenous epoprostenol or intravenous treprostinil for pulmonary arterial hypertension--seven sites, United States, 2003-2006.
2007 Mar 2
Treprostinil for pulmonary hypertension.
2008
Primary pulmonary hypertension as a manifestation of adult multi-system mitochondrial disorder.
2009 Apr 30
Gateways to clinical trials.
2009 Sep
Stability and antimicrobial effectiveness of treprostinil sodium in Sterile Diluent for Flolan.
2010 Jun
The PPARbeta/delta agonist GW0742 relaxes pulmonary vessels and limits right heart hypertrophy in rats with hypoxia-induced pulmonary hypertension.
2010 Mar 4
The Adult Patient with Eisenmenger Syndrome: A Medical Update after Dana Point Part II: Medical Treatment - Study Results.
2010 Nov
Binding and activity of the prostacyclin receptor (IP) agonists, treprostinil and iloprost, at human prostanoid receptors: treprostinil is a potent DP1 and EP2 agonist.
2012 Jul 1
Patents

Sample Use Guides

In Vivo Use Guide
Curator's Comment: Treprostinil is available in three different formulations and four different routes of administration: Remodulin® (treprostinil sodium, intravenous and subcutaneous administration), Tyvaso® (treprostinil sodium, inhaled administration), and Orenitram® (treprostinil diolamine, oral administration) for the treatment of pulmonary arterial hypertension (PAH). https://www.ncbi.nlm.nih.gov/pubmed/?term=27286723
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
Curator's Comment: Treprostinil (0.15 - 15 ng/ml) slightly increased contractile dynamics of cardiomyocytes at clinically relevant concentrations.
Treprostinil (0.15 - 15 ng/ml) rat cardiomyocytes
Substance Class Chemical
Created
by admin
on Fri Dec 15 15:51:30 GMT 2023
Edited
by admin
on Fri Dec 15 15:51:30 GMT 2023
Record UNII
7JZ75N2NT6
Record Status Validated (UNII)
Record Version
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Name Type Language
TREPROSTINIL SODIUM
MART.   ORANGE BOOK   WHO-DD  
Common Name English
TREPROSTINIL SODIUM SALT
MI  
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
Created by admin on Fri Dec 15 15:51:30 GMT 2023 , Edited by admin on Fri Dec 15 15:51:30 GMT 2023
EU-Orphan Drug EU/3/04/197
Created by admin on Fri Dec 15 15:51:30 GMT 2023 , Edited by admin on Fri Dec 15 15:51:30 GMT 2023
NCI_THESAURUS C270
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FDA ORPHAN DRUG 478815
Created by admin on Fri Dec 15 15:51:30 GMT 2023 , Edited by admin on Fri Dec 15 15:51:30 GMT 2023
Code System Code Type Description
FDA UNII
7JZ75N2NT6
Created by admin on Fri Dec 15 15:51:30 GMT 2023 , Edited by admin on Fri Dec 15 15:51:30 GMT 2023
PRIMARY
DRUG BANK
DBSALT002321
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PRIMARY
RXCUI
342691
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PRIMARY RxNorm
CAS
289480-64-4
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PRIMARY
MESH
C427248
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PRIMARY
EVMPD
SUB22911
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PRIMARY
PUBCHEM
23663413
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PRIMARY
SMS_ID
100000086898
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PRIMARY
NCI_THESAURUS
C61984
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PRIMARY
MERCK INDEX
m11018
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PRIMARY Merck Index
DAILYMED
7JZ75N2NT6
Created by admin on Fri Dec 15 15:51:30 GMT 2023 , Edited by admin on Fri Dec 15 15:51:30 GMT 2023
PRIMARY
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