Details
| Stereochemistry | ABSOLUTE |
| Molecular Formula | C23H36O11P2 |
| Molecular Weight | 550.4729 |
| Optical Activity | UNSPECIFIED |
| Defined Stereocenters | 5 / 5 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
[H][C@]12C[C@@H](OP(O)(O)=O)[C@H](CC[C@H](CCCCC)OP(O)(O)=O)[C@@]1([H])CC3=CC=CC(OCC(O)=O)=C3C2
InChI
InChIKey=IERCXWVEMYXPMR-KSSXRGRSSA-N
InChI=1S/C23H36O11P2/c1-2-3-4-7-17(33-35(26,27)28)9-10-18-19-11-15-6-5-8-21(32-14-23(24)25)20(15)12-16(19)13-22(18)34-36(29,30)31/h5-6,8,16-19,22H,2-4,7,9-14H2,1H3,(H,24,25)(H2,26,27,28)(H2,29,30,31)/t16-,17-,18+,19-,22+/m0/s1
DescriptionCurator'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/
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
Targets
| Primary Target | Pharmacology | Condition | Potency |
|---|---|---|---|
Target ID: CHEMBL1995 |
32.0 nM [Ki] | ||
Target ID: CHEMBL4427 |
4.4 nM [Ki] | ||
Target ID: CHEMBL1881 |
3.6 nM [Ki] | ||
Target ID: CHEMBL3979 |
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| Primary | REMODULIN Approved UseRemodulin 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 Date2002 |
Cmax
| 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 |
T1/2
| 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 |
Funbound
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
9% |
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) Sources: lasix(40 mg) coumadin(4 mg) |
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) Sources: Blurred vision (1 patient) |
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) Sources: Throat irritation (26 patients) |
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) Sources: Tachycardia (1 patient) Arrhythmia ventricular (1 patient) Dyspnea (1 patient) |
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
| 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) Sources: lasix(40 mg) coumadin(4 mg) |
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) Sources: lasix(40 mg) coumadin(4 mg) |
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
| CYP3A4 | CYP2C9 | CYP2D6 | hERG |
|---|---|---|---|
OverviewOther
| Other Inhibitor | Other Substrate | Other Inducer |
|---|---|---|
Drug as perpetrator
| Target | Modality | Activity | Metabolite | Clinical evidence |
|---|---|---|---|---|
| no | ||||
| no | ||||
| no | ||||
| no | ||||
| no |
Drug as victim
| Target | Modality | Activity | Metabolite | Clinical 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
| Target | Modality | Activity | Metabolite | Clinical evidence |
|---|---|---|---|---|
PubMed
| Title | Date | PubMed |
|---|---|---|
| Treprostinil sodium Pharmacia. | 2002 Apr |
|
| Gateways to clinical trials. | 2002 Dec |
|
| Stability and preservative effectiveness of treprostinil sodium after dilution in common intravenous diluents. | 2003 May 1 |
|
| Gateways to clinical trials. | 2003 Sep |
|
| 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 |
|
| Treprostinil for pulmonary hypertension. | 2004 Mar |
|
| Overview of treprostinil sodium for the treatment of pulmonary arterial hypertension. | 2004 Mar |
|
| Gateways to clinical trials. | 2004 Mar |
|
| Pharmacokinetics of treprostinil sodium administered by 28-day chronic continuous subcutaneous infusion. | 2004 May |
|
| Staggered transition to epoprostenol from treprostinil in pulmonary arterial hypertension. | 2005 Apr |
|
| Gateways to clinical trials. | 2005 Dec |
|
| Gateways to clinical trials. | 2005 Jan-Feb |
|
| Gateways to clinical trials. | 2005 Jun |
|
| Gateways to clinical trials. | 2005 Sep |
|
| Role of prostacyclin versus peroxisome proliferator-activated receptor beta receptors in prostacyclin sensing by lung fibroblasts. | 2006 Feb |
|
| [The best of clinical cardiovascular pharmacology in 2005]. | 2006 Jan |
|
| 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 |
|
| IP receptor-dependent activation of PPARgamma by stable prostacyclin analogues. | 2007 Sep 7 |
|
| Patient safety challenges in treprostinil therapy. | 2008 Apr |
|
| A novel catheter system for totally implantable intravenous drug therapy: assessment of catheter function and patency with trepostinil therapy. | 2008 Jan-Mar |
|
| Gateways to clinical trials. | 2009 Sep |
|
| Smad-dependent and smad-independent induction of id1 by prostacyclin analogues inhibits proliferation of pulmonary artery smooth muscle cells in vitro and in vivo. | 2010 Jul 23 |
|
| The PPARbeta/delta agonist GW0742 relaxes pulmonary vessels and limits right heart hypertrophy in rats with hypoxia-induced pulmonary hypertension. | 2010 Mar 4 |
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
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Systematic Name | English |
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LM-105
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830354-49-9
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156104640
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99S2PY5BN2
Created by
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ACTIVE MOIETY
SUBSTANCE RECORD
