Identification

Summary

Treprostinil is a prostacyclin vasodilator for the treatment of pulmonary arterial hypertension to relieve exercise associated symptoms and to prevent clinical deterioration after stopping epoprostenol.

Brand Names
Orenitram, Remodulin, Tyvaso
Generic Name
Treprostinil
DrugBank Accession Number
DB00374
Background

Treprostinil is a stable tricyclic analogue of prostacyclin3 that promotes the vasodilation of pulmonary and systemic arterial vascular beds and the inhibition of platelet aggregation.5,6,7 It reduces symptoms in patients with pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with interstitial lung disease.5,6 The first agent approved for the treatment of PAH was epoprostenol, a synthetic prostacyclin that significantly increases patients' quality of life. However, the use of epoprostenol is limited due to its short half-life (3-5 min) and instability at room temperature.3,4 The use of more stable alternatives such as treprostinil provides patients with PAH with more treatment options.

Treprostinil was approved by the FDA in 2002 for the treatment of pulmonary arterial hypertension.6 It is available in the following routes of administration: subcutaneous, intravenous, inhaled and oral. The first generic form of treprostinil became available in 2019.4

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 390.5131
Monoisotopic: 390.240624198
Chemical Formula
C23H34O5
Synonyms
  • Treprostinil
  • Tréprostinil
  • Treprostinilo
  • Treprostinilum
External IDs
  • 15AU81
  • BW 15AU
  • LRX 15
  • LRX-15
  • U 62840
  • UT 15
  • UT-15
  • UT-15C

Pharmacology

Indication

Treprostinil is indicated for the treatment of pulmonary arterial hypertension5,6,7 and pulmonary hypertension associated with interstitial lung disease5 to improve exercise ability. It is also used to treat pulmonary arterial hypertension in patients requiring transition from epoprostenol.6

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

As an analogue of prostacyclin, treprostinil promotes the vasodilation of pulmonary and systemic arterial vascular beds and the inhibition of platelet aggregation 5,6,7. In animals, the vasodilatory effects of treprostinil lead to a reduction of right and left ventricular afterload and an increase in cardiac output and stroke volume.6 Treprostinil also causes a dose-related negative inotropic and lusitropic effect, and no major effects on cardiac conduction have been detected.6 Short-lasting effects on QTc were detected in healthy volunteers (n=240) given inhaled single doses of 54 and 84 μg of treprostinil. These effects dissipated rapidly as treprostinil concentrations lowered.5 When given subcutaneously or intravenously, treprostinil has the potential to reach higher concentrations.6 The effect of oral treprostinil on QTc has not been evaluated.7

Due to its ability to inhibit platelet aggregation, treprostinil can increase the risk of bleeding, and patients with low systemic arterial pressure taking treprostinil may experience symptomatic hypotension.5,6 The abrupt withdrawal of treprostinil or drastic changes in dose may worsen the symptoms of pulmonary arterial hypertension (PAH).6,7 The inhalation of treprostinil can also cause bronchospasms in patients with asthma, chronic obstructive pulmonary disease (COPD), or bronchial hyperreactivity.5 When given intravenously, treprostinil can lead to infusion complications and increase the risk of bloodstream infections.6

Mechanism of action

Treprostinil is a stable analogue of prostacyclin5,6,7, a prostaglandin that acts as an anti-thrombotic agent and a potent vasodilator. Prostacyclin analogues are useful in the treatment of pulmonary arterial hypertension (PAH), a disease characterized by abnormally high blood pressure in the arteries between the heart and lungs.3 PAH leads to right heart failure due to the remodelling of pulmonary arteries, and patients with this condition have a poor prognosis.4

Treprostinil binds and activates the prostacyclin receptor, the prostaglandin D2 receptor 1, and the prostaglandin E2 receptor 2.3 The activation of these receptors leads to the elevation of intracellular cyclic adenosine monophosphate (cAMP) levels, which consequently promotes the opening of calcium-activated potassium channels that lead to cell hyperpolarization.3 This mechanism promotes the direct vasodilation of pulmonary and systemic arterial vascular beds and the inhibition of platelet aggregation1,5,6,7. In addition to its direct vasodilatory effects, treprostinil inhibits inflammatory pathways.2

TargetActionsOrganism
AProstacyclin receptor
agonist
Humans
AProstaglandin E2 receptor EP2 subtype
agonist
Humans
AProstaglandin D2 receptor
agonist
Humans
APeroxisome proliferator-activated receptor delta
agonist
Humans
UP2Y purinoceptor 12
agonist
Humans
Absorption

After subcutaneous infusion, treprostinil is completely absorbed, with a bioavailability of about 100%, and it reaches steady-state concentrations in approximately 10 hours.6 The pharmacokinetics of treprostinil follow a two-compartment model and are linear between 2.5 and 125 ng/kg/min.6 Subcutaneous and intravenous doses of treprostinil are bioequivalent at 10 ng/kg/min. Compared to healthy subjects, patients with mild and moderate hepatic insufficiency had a corresponding Cmax 2- and 4-times higher and an AUC0-∞ 3- and 5-times higher when given a subcutaneous treprostinil dose of 10 ng/kg/min for 150 min.6

When given orally at doses between 0.5 and 15 mg twice a day, treprostinil follows a dose-proportional pharmacokinetic profile.7 The oral bioavailability of treprostinil is 17%, and drug concentration reaches its highest level between 4 and 6 hours after oral administration.7 The oral absorption of treprostinil is affected by food. The AUC and Cmax of oral treprostinil increase 49% and 13%, respectively, when this drug is administered with a high-fat, high-calorie meal.7

The AUC and Cmax of inhaled treprostinil were proportional to the doses administered (18 to 90 μg).5 The bioavailability of inhaled treprostinil was 64% in patients receiving 2 doses of 18 μg, and 72% in patients receiving two doses of 36 μg.5 Two separate studies that evaluated the pharmacokinetics of inhaled treprostinil at a maintenance dose of 54 μg found that the mean Cmax was 0.91 and 1.32 ng/mL, respectively, with a corresponding Tmax of 0.25 and 0.12 hr and a mean AUC of 0.81 and 0.97 hr⋅ng/mL.5

Volume of distribution

The volume of distribution of treprostinil is 14 L/70 kg.5,6

Protein binding

At in vitro concentrations ranging from 330 to 10,000 μg/L, the human plasma protein binding of treprostinil is approximately 91%. This concentration is above what is considered to be clinically relevant.6

Metabolism

Treprostinil is mostly metabolized by the liver, mainly by CYP2C8, and by CYP2C9 to a lesser extent.5,6,7 Treprostinil does not have a single major metabolite. The five metabolites detected in urine (HU1 through HU5) accounted for 13.8, 14.3, 15.5, 10.6 and 10.2% of the dose, respectively.8 One of the metabolites (HU5) is the glucuronide conjugate of treprostinil. HU1, HU2, HU3 and HU4 are formed through the oxidation of the 3-hydroxyloctyl side chain.5,6,7,8 None of the metabolites of treprostinil appear to be active. In vitro studies suggest that treprostinil does not inhibit or induce any major CYP enzymes.5,6

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Route of elimination

Treprostinil metabolites are excreted through urine (79%) and feces (13%) over 10 days.5,6 Only a small proportion of treprostinil is excreted unchanged. When administered orally, 1.13% and 0.19% of unchanged treprostinil diolamine are found in urine and feces, respectively.7 When administered subcutaneously, intravenously or by inhalation, 4% of unchanged treprostinil is found in urine.5,6

Half-life

The terminal elimination half-life of treprostinil is approximately 4 hours, following a two-compartment model.5,6

Clearance

The clearance of treprostinil is 30 L/hr in a 70 kg person.6 In patients with mild to moderate hepatic insufficiency, clearance is reduced up to 80%.5

Adverse Effects
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Toxicity

Treprostinil overdose symptoms are an extension of its dose-limiting pharmacologic effects.6 These include flushing, headache, hypotension, nausea, vomiting, and diarrhea.5,6,7 Most overdose events were self-limiting and resolved by reducing or withholding treprostinil.6 In studies where treprostinil was infused using an external pump, several patients received an overdose due to an accidental bolus administration, errors in the programmed delivery rate and incorrect prescriptions. Only two cases of of substantial hemodynamic concern were detected among patients that received an excess of treprostinil.6 A pediatric patient that accidentally received 7.5 mg of treprostinil via a central venous catheter presented flushing, headache, nausea, vomiting, hypotension, and seizure-like activity with loss of consciousness for several minutes.6

A rat study that evaluated the carcinogenic effects of inhaled treprostinil, found no evidence of carcinogenicity in levels up to 35 times the clinical exposure obtained with a maintenance dose of 54 μg.5 The infusion of treprostinil sodium did not affect fertility or mating performance in rats given subcutaneous treprostinil.6 Treprostinil did not show mutagenic or clastogenic effects in in vitro or in vivo studies.5,6 There was no significant increase of tumors in rats given up to 10 mg/kg/day of oral treprostinil diolamine.7

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbataceptThe metabolism of Treprostinil can be increased when combined with Abatacept.
AbciximabTreprostinil may increase the antiplatelet activities of Abciximab.
AbirateroneThe metabolism of Treprostinil can be decreased when combined with Abiraterone.
AbrocitinibThe metabolism of Abrocitinib can be decreased when combined with Treprostinil.
AcebutololTreprostinil may increase the hypotensive activities of Acebutolol.
AceclofenacThe risk or severity of bleeding can be increased when Treprostinil is combined with Aceclofenac.
AcemetacinThe risk or severity of bleeding can be increased when Treprostinil is combined with Acemetacin.
AcenocoumarolThe risk or severity of bleeding can be increased when Treprostinil is combined with Acenocoumarol.
AcetohexamideThe metabolism of Acetohexamide can be decreased when combined with Treprostinil.
Acetyl sulfisoxazoleThe metabolism of Treprostinil can be decreased when combined with Acetyl sulfisoxazole.
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Food Interactions
  • Take with food. Taking treprostinil with food increases oral absorption.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Treprostinil diolamineH1FKG90039830354-48-8RHWRWEUCEXUUAV-ZSESPEEFSA-N
Treprostinil sodium7JZ75N2NT6289480-64-4IQKAWAUTOKVMLE-ZSESPEEFSA-M
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
OrenitramTablet, extended release2.5 mg/1OralAvera McKennan Hospital2016-07-202017-05-24US flag
OrenitramTablet, extended release1 mg/1OralUnited Therapeutics Corporation2013-12-20Not applicableUS flag
OrenitramTablet, extended release5 mg/1OralUnited Therapeutics Corporation2013-12-20Not applicableUS flag
OrenitramTablet, extended release0.25 mg/1OralUnited Therapeutics Corporation2013-12-20Not applicableUS flag
OrenitramTablet, extended release2.5 mg/1OralUnited Therapeutics Corporation2013-12-20Not applicableUS flag
OrenitramTablet, extended release0.125 mg/1OralUnited Therapeutics Corporation2013-12-20Not applicableUS flag
RemodulinInjection, solution50 mg/20mLIntravenous; SubcutaneousUnited Therapeutics Corporation2002-05-22Not applicableUS flag
RemodulinSolution2.5 mg / mLIntravenous; SubcutaneousUnited Therapeutics Corporation2004-04-30Not applicableCanada flag
RemodulinInjection, solution200 mg/20mLIntravenous; SubcutaneousUnited Therapeutics Corporation2002-05-22Not applicableUS flag
RemodulinSolution10 mg / mLIntravenous; SubcutaneousUnited Therapeutics Corporation2004-04-30Not applicableCanada flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TreprostinilInjection100 mg/20mLIntravenous; SubcutaneousSandoz Inc2019-03-25Not applicableUS flag
TreprostinilInjection, solution200 mg/20mLIntravenous; SubcutaneousTeva Parenteral Medicines, Inc.2019-09-30Not applicableUS flag
TreprostinilInjection, solution20 mg/20mLIntravenous; SubcutaneousTeva Parenteral Medicines, Inc.2019-09-30Not applicableUS flag
TreprostinilInjection, solution200 mg/20mLIntravenous; SubcutaneousAlembic Pharmaceuticals Inc.2021-02-11Not applicableUS flag
TreprostinilInjection, solution5 mg/1mLIntravenous; SubcutaneousPar Pharmaceutical, Inc.2019-09-25Not applicableUS flag
TreprostinilInjection, solution20 mg/20mLIntravenous; SubcutaneousAlembic Pharmaceuticals Inc.2021-02-11Not applicableUS flag
TreprostinilInjection50 mg/20mLIntravenous; SubcutaneousSandoz Inc2019-03-25Not applicableUS flag
TreprostinilInjection, solution100 mg/20mLIntravenous; SubcutaneousTeva Parenteral Medicines, Inc.2019-09-30Not applicableUS flag
TreprostinilInjection, solution1 mg/1mLIntravenous; SubcutaneousPar Pharmaceutical, Inc.2019-09-25Not applicableUS flag
TreprostinilInjection, solution100 mg/20mLIntravenous; SubcutaneousAlembic Pharmaceuticals Inc.2021-02-11Not applicableUS flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Tyvaso DPITreprostinil (16 ug/1) + Treprostinil (32 ug/1) + Treprostinil (48 ug/1)Inhalant; KitOralUnited Therapeutics Corporation2022-05-23Not applicableUS flag
Tyvaso DPITreprostinil (32 ug/1) + Treprostinil (48 ug/1)Inhalant; KitOralUnited Therapeutics Corporation2022-05-23Not applicableUS flag
Tyvaso DPITreprostinil (16 ug/1) + Treprostinil (32 ug/1)Inhalant; KitOralUnited Therapeutics Corporation2022-05-23Not applicableUS flag
Tyvaso DPITreprostinil (16 ug/1) + Treprostinil (32 ug/1) + Treprostinil (48 ug/1)Inhalant; KitOralUnited Therapeutics Corporation2022-05-23Not applicableUS flag
Tyvaso DPITreprostinil (32 ug/1) + Treprostinil (48 ug/1)Inhalant; KitOralUnited Therapeutics Corporation2022-05-23Not applicableUS flag
Tyvaso DPITreprostinil (16 ug/1) + Treprostinil (32 ug/1)Inhalant; KitOralUnited Therapeutics Corporation2022-05-23Not applicableUS flag
Tyvaso DPITreprostinil (16 ug/1) + Treprostinil (32 ug/1) + Treprostinil (48 ug/1)Inhalant; KitOralUnited Therapeutics Corporation2022-05-23Not applicableUS flag
Tyvaso DPITreprostinil (32 ug/1) + Treprostinil (48 ug/1)Inhalant; KitOralUnited Therapeutics Corporation2022-05-23Not applicableUS flag
Tyvaso DPITreprostinil (32 ug/1) + Treprostinil (48 ug/1)Inhalant; KitOralUnited Therapeutics Corporation2022-05-23Not applicableUS flag

Categories

ATC Codes
B01AC21 — Treprostinil
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as phenoxyacetic acid derivatives. These are compounds containing an anisole where the methane group is linked to an acetic acid or a derivative.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Phenoxyacetic acid derivatives
Direct Parent
Phenoxyacetic acid derivatives
Alternative Parents
Tetralins / Fatty alcohols / Alkyl aryl ethers / Secondary alcohols / Cyclic alcohols and derivatives / Monocarboxylic acids and derivatives / Carboxylic acids / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
Substituents
Alcohol / Alkyl aryl ether / Aromatic homopolycyclic compound / Carbonyl group / Carboxylic acid / Carboxylic acid derivative / Cyclic alcohol / Ether / Fatty acyl / Fatty alcohol
Molecular Framework
Aromatic homopolycyclic compounds
External Descriptors
carboxylic acid, carbotricyclic compound (CHEBI:50861)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
RUM6K67ESG
CAS number
81846-19-7
InChI Key
PAJMKGZZBBTTOY-ZFORQUDYSA-N
InChI
InChI=1S/C23H34O5/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)/t16-,17-,18+,19-,21+/m0/s1
IUPAC Name
2-{[(1R,2R,3aS,9aS)-2-hydroxy-1-[(3S)-3-hydroxyoctyl]-1H,2H,3H,3aH,4H,9H,9aH-cyclopenta[b]naphthalen-5-yl]oxy}acetic acid
SMILES
[H][C@]12C[C@@H](O)[C@H](CC[C@@H](O)CCCCC)[C@@]1([H])CC1=C(C2)C(OCC(O)=O)=CC=C1

References

Synthesis Reference

Hitesh, B., et al. (2015). Treprostinil production (U.S. Patent No. 8,940,930 B2) U.S. Patent and Trademark Office. https://patentimages.storage.googleapis.com/1d/63/6e/c2a1143b85274e/US8940930.pdf

US20110319641
General References
  1. Del Pozo R, Hernandez Gonzalez I, Escribano-Subias P: The prostacyclin pathway in pulmonary arterial hypertension: a clinical review. Expert Rev Respir Med. 2017 Jun;11(6):491-503. doi: 10.1080/17476348.2017.1317599. Epub 2017 Apr 24. [Article]
  2. Ding M, Tolbert E, Birkenbach M, Akhlaghi F, Gohh R, Ghonem NS: Treprostinil, a prostacyclin analog, ameliorates renal ischemia-reperfusion injury: preclinical studies in a rat model of acute kidney injury. Nephrol Dial Transplant. 2021 Jan 25;36(2):257-266. doi: 10.1093/ndt/gfaa236. [Article]
  3. Lindegaard Pedersen M, Kruger M, Grimm D, Infanger M, Wehland M: The prostacyclin analogue treprostinil in the treatment of pulmonary arterial hypertension. Basic Clin Pharmacol Toxicol. 2019 Aug 12. doi: 10.1111/bcpt.13305. [Article]
  4. Feldman J, Habib N, Fann J, Radosevich JJ: Treprostinil in the treatment of pulmonary arterial hypertension. Future Cardiol. 2020 Nov;16(6):547-558. doi: 10.2217/fca-2020-0021. Epub 2020 May 11. [Article]
  5. FDA Approved Drug Products: TYVASO (treprostinil) inhalation solution, for oral inhalation use [Link]
  6. FDA Approved Drug Products: REMODULIN (treprostinil) injection, for subcutaneous or intravenous use [Link]
  7. FDA Approved Drug Products: ORENITRAM (treprostinil) extended-release tablets, for oral use [Link]
  8. FDA Pharmacology Review: REMODULIN (treprostinil) injection, for subcutaneous or intravenous use [Link]
  9. Par Pharmaceutical: Treprostinil SDS [Link]
  10. FDA Clinical Pharmacology and Biopharmaceutics Review: ORENITRAM (treprostinil) extended-release tablets, for oral use [Link]
Human Metabolome Database
HMDB0014518
PubChem Compound
6918140
PubChem Substance
46504572
ChemSpider
5293353
RxNav
343048
ChEBI
50861
ChEMBL
CHEMBL1237119
ZINC
ZINC000003800475
Therapeutic Targets Database
DAP001214
PharmGKB
PA164768801
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Treprostinil

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentPulmonary Arterial Hypertension (PAH)5
4CompletedTreatmentPulmonary Arterial Hypertension (PAH) / Pulmonary Hypertension (PH)1
4CompletedTreatmentPulmonary Hypertension (PH)2
4Not Yet RecruitingTreatmentPulmonary Arterial Hypertension (PAH)1
4RecruitingOtherPulmonary Hypertension (PH)1
4TerminatedTreatmentPulmonary Arterial Hypertension (PAH)2
4TerminatedTreatmentPulmonary Hypertension (PH)2
4WithdrawnTreatmentPulmonary Arterial Hypertension (PAH)3
3Active Not RecruitingTreatmentPulmonary Hypertension, Primary1
3CompletedNot AvailablePulmonary Arterial Hypertension (PAH)1

Pharmacoeconomics

Manufacturers
  • United therapeutics corp
Packagers
  • Baxter International Inc.
  • United Therapeutics Corp.
Dosage Forms
FormRouteStrength
Tablet, extended releaseOral0.125 mg/1
Tablet, extended releaseOral0.25 mg/1
Tablet, extended releaseOral1 mg/1
Tablet, extended releaseOral2.5 mg/1
Tablet, extended releaseOral5 mg/1
Injection, solutionIntravenous; Subcutaneous100 mg/20mL
Injection, solutionIntravenous; Subcutaneous20 mg/20mL
Injection, solutionIntravenous; Subcutaneous200 mg/20mL
Injection, solutionIntravenous; Subcutaneous400 mg/20mL
Injection, solutionIntravenous; Subcutaneous50 mg/20mL
Injection, solutionParenteral5 MG/ML
SolutionIntravenous; Subcutaneous1 mg / mL
SolutionIntravenous; Subcutaneous10 mg / mL
SolutionIntravenous; Subcutaneous2.5 mg / mL
SolutionIntravenous; Subcutaneous5 mg / mL
SolutionIntravenous; Subcutaneous1 mg
SolutionIntravenous; Subcutaneous10 mg
SolutionIntravenous; Subcutaneous5 mg
SolutionParenteral
SolutionIntravenous; Subcutaneous2.5 mg
InjectionIntravenous; Subcutaneous100 mg/20mL
InjectionIntravenous; Subcutaneous20 mg/20mL
InjectionIntravenous; Subcutaneous200 mg/20mL
InjectionIntravenous; Subcutaneous50 mg/20mL
Injection, solutionIntravenous; Subcutaneous1 mg/1mL
Injection, solutionIntravenous; Subcutaneous10 mg/1mL
Injection, solutionIntravenous; Subcutaneous2.5 mg/1mL
Injection, solutionIntravenous; Subcutaneous5 mg/1mL
SolutionParenteral1 mg/ml
SolutionParenteral10 mg/ml
SolutionParenteral2.5 mg/ml
SolutionParenteral5 mg/ml
Injection, solutionParenteral1 MG/ML
Injection, solutionParenteral10 MG/ML
Injection, solutionParenteral2.5 MG/ML
Injection, solutionParenteral4 MG/ML
Injection, solution1 MG/ML
Injection, solution10 MG/ML
Injection, solution2.5 MG/ML
Injection, solution5 MG/ML
Injection, solutionSubcutaneous1 MG/ML
Injection, solutionSubcutaneous10 MG/ML
Injection, solutionSubcutaneous2.5 MG/ML
Injection, solutionSubcutaneous5 MG/ML
InhalantOral1.74 mg/2.9mL
InhalantOral16 ug/1
InhalantOral32 ug/1
InhalantOral48 ug/1
InhalantOral64 ug/1
Inhalant; kitOral
Prices
Unit descriptionCostUnit
Remodulin 10 mg/ml vial737.0USD ml
Remodulin 5 mg/ml vial368.5USD ml
Tyvaso inhalation starter kit185.8USD ml
Remodulin 2.5 mg/ml vial184.25USD ml
Tyvaso 1.74 mg/2.9 ml solution174.55USD ml
Tyvaso inhalation refill kit165.68USD ml
Remodulin 1 mg/ml vial73.7USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US5153222No1992-10-062014-10-06US flag
US8653137No2014-02-182028-09-05US flag
US8658694No2014-02-252028-09-05US flag
US7999007No2011-08-162029-03-29US flag
US9199908No2015-12-012024-05-24US flag
US6765117No2004-07-202017-10-24US flag
US8497393No2013-07-302028-12-15US flag
US6521212No2003-02-182018-11-13US flag
US6756033No2004-06-292018-11-13US flag
US7544713No2009-06-092024-07-14US flag
US9278901No2016-03-082024-05-24US flag
US7417070No2008-08-262026-07-30US flag
US8410169No2013-04-022030-02-13US flag
US9050311No2015-06-092024-05-24US flag
US8252839No2012-08-282024-05-24US flag
US8747897No2014-06-102029-10-08US flag
US8349892No2013-01-082031-01-22US flag
US9593066No2017-03-142028-12-15US flag
US9604901No2017-03-282028-12-15US flag
US9339507No2016-05-172028-03-10US flag
US9358240No2016-06-072028-05-05US flag
US9422223No2016-08-232024-05-24US flag
US9393203No2016-07-192026-04-27US flag
US9713599No2017-07-252024-12-16US flag
US10076505No2018-09-182024-12-16US flag
US10376525No2019-08-132027-05-14US flag
US10716793No2020-07-212027-05-14US flag
US10695308No2020-06-302024-12-16US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)90-100°CSDS
water solubility800 mg/mLFDA Clinical Pharmacology and Biopharmaceutics Review: ORENITRAM (treprostinil) extended-release tablets, for oral use
logP3FDA Clinical Pharmacology and Biopharmaceutics Review: ORENITRAM (treprostinil) extended-release tablets, for oral use
Predicted Properties
PropertyValueSource
Water Solubility0.00731 mg/mLALOGPS
logP3.53ALOGPS
logP4ChemAxon
logS-4.7ALOGPS
pKa (Strongest Acidic)3.76ChemAxon
pKa (Strongest Basic)-1.3ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area86.99 Å2ChemAxon
Rotatable Bond Count10ChemAxon
Refractivity108 m3·mol-1ChemAxon
Polarizability45.75 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.994
Blood Brain Barrier+0.5541
Caco-2 permeable+0.5838
P-glycoprotein substrateSubstrate0.7733
P-glycoprotein inhibitor INon-inhibitor0.719
P-glycoprotein inhibitor IINon-inhibitor0.7518
Renal organic cation transporterNon-inhibitor0.8064
CYP450 2C9 substrateNon-substrate0.7811
CYP450 2D6 substrateNon-substrate0.8144
CYP450 3A4 substrateSubstrate0.6538
CYP450 1A2 substrateInhibitor0.7312
CYP450 2C9 inhibitorNon-inhibitor0.8496
CYP450 2D6 inhibitorNon-inhibitor0.9127
CYP450 2C19 inhibitorNon-inhibitor0.6214
CYP450 3A4 inhibitorNon-inhibitor0.6587
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6885
Ames testNon AMES toxic0.8716
CarcinogenicityNon-carcinogens0.9452
BiodegradationNot ready biodegradable0.7495
Rat acute toxicity2.0749 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9588
hERG inhibition (predictor II)Inhibitor0.7664
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Guanyl-nucleotide exchange factor activity
Specific Function
Receptor for prostacyclin (prostaglandin I2 or PGI2). The activity of this receptor is mediated by G(s) proteins which activate adenylate cyclase.
Gene Name
PTGIR
Uniprot ID
P43119
Uniprot Name
Prostacyclin receptor
Molecular Weight
40955.485 Da
References
  1. Falcetti E, Hall SM, Phillips PG, Patel J, Morrell NW, Haworth SG, Clapp LH: Smooth muscle proliferation and role of the prostacyclin (IP) receptor in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2010 Nov 1;182(9):1161-70. doi: 10.1164/rccm.201001-0011OC. Epub 2010 Jul 9. [Article]
  2. Sprague RS, Bowles EA, Hanson MS, DuFaux EA, Sridharan M, Adderley S, Ellsworth ML, Stephenson AH: Prostacyclin analogs stimulate receptor-mediated cAMP synthesis and ATP release from rabbit and human erythrocytes. Microcirculation. 2008 Jul;15(5):461-71. doi: 10.1080/10739680701833804. [Article]
  3. Olschewski H, Rose F, Schermuly R, Ghofrani HA, Enke B, Olschewski A, Seeger W: Prostacyclin and its analogues in the treatment of pulmonary hypertension. Pharmacol Ther. 2004 May;102(2):139-53. [Article]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  5. Lindegaard Pedersen M, Kruger M, Grimm D, Infanger M, Wehland M: The prostacyclin analogue treprostinil in the treatment of pulmonary arterial hypertension. Basic Clin Pharmacol Toxicol. 2019 Aug 12. doi: 10.1111/bcpt.13305. [Article]
  6. Del Pozo R, Hernandez Gonzalez I, Escribano-Subias P: The prostacyclin pathway in pulmonary arterial hypertension: a clinical review. Expert Rev Respir Med. 2017 Jun;11(6):491-503. doi: 10.1080/17476348.2017.1317599. Epub 2017 Apr 24. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Prostaglandin e receptor activity
Specific Function
Receptor for prostaglandin E2 (PGE2). The activity of this receptor is mediated by G(s) proteins that stimulate adenylate cyclase. The subsequent raise in intracellular cAMP is responsible for the ...
Gene Name
PTGER2
Uniprot ID
P43116
Uniprot Name
Prostaglandin E2 receptor EP2 subtype
Molecular Weight
39759.945 Da
References
  1. Lindegaard Pedersen M, Kruger M, Grimm D, Infanger M, Wehland M: The prostacyclin analogue treprostinil in the treatment of pulmonary arterial hypertension. Basic Clin Pharmacol Toxicol. 2019 Aug 12. doi: 10.1111/bcpt.13305. [Article]
  2. Del Pozo R, Hernandez Gonzalez I, Escribano-Subias P: The prostacyclin pathway in pulmonary arterial hypertension: a clinical review. Expert Rev Respir Med. 2017 Jun;11(6):491-503. doi: 10.1080/17476348.2017.1317599. Epub 2017 Apr 24. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Prostaglandin j receptor activity
Specific Function
Receptor for prostaglandin D2 (PGD2). The activity of this receptor is mainly mediated by G(s) proteins that stimulate adenylate cyclase, resulting in an elevation of intracellular cAMP. A mobiliza...
Gene Name
PTGDR
Uniprot ID
Q13258
Uniprot Name
Prostaglandin D2 receptor
Molecular Weight
40270.11 Da
References
  1. Lindegaard Pedersen M, Kruger M, Grimm D, Infanger M, Wehland M: The prostacyclin analogue treprostinil in the treatment of pulmonary arterial hypertension. Basic Clin Pharmacol Toxicol. 2019 Aug 12. doi: 10.1111/bcpt.13305. [Article]
  2. Del Pozo R, Hernandez Gonzalez I, Escribano-Subias P: The prostacyclin pathway in pulmonary arterial hypertension: a clinical review. Expert Rev Respir Med. 2017 Jun;11(6):491-503. doi: 10.1080/17476348.2017.1317599. Epub 2017 Apr 24. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Zinc ion binding
Specific Function
Ligand-activated transcription factor. Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Has a preference for poly-unsaturated fatty acids, such as gamma-lin...
Gene Name
PPARD
Uniprot ID
Q03181
Uniprot Name
Peroxisome proliferator-activated receptor delta
Molecular Weight
49902.99 Da
References
  1. Ali FY, Egan K, FitzGerald GA, Desvergne B, Wahli W, Bishop-Bailey D, Warner TD, Mitchell JA: Role of prostacyclin versus peroxisome proliferator-activated receptor beta receptors in prostacyclin sensing by lung fibroblasts. Am J Respir Cell Mol Biol. 2006 Feb;34(2):242-6. Epub 2005 Oct 20. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
Curator comments
The resource suggests that treprostinil inhibits platelet activation following a mechanism similar to the one promoted by anti-P2Y12 molecules. However, an interaction between treprostinil and P2Y12 remains to be validated.
General Function
Guanyl-nucleotide exchange factor activity
Specific Function
Receptor for ADP and ATP coupled to G-proteins that inhibit the adenylyl cyclase second messenger system. Not activated by UDP and UTP. Required for normal platelet aggregation and blood coagulation.
Gene Name
P2RY12
Uniprot ID
Q9H244
Uniprot Name
P2Y purinoceptor 12
Molecular Weight
39438.355 Da
References
  1. Bacha NC, Levy M, Guerin CL, Le Bonniec B, Harroche A, Szezepanski I, Renard JM, Gaussem P, Israel-Biet D, Boulanger CM, Smadja DM: Treprostinil treatment decreases circulating platelet microvesicles and their procoagulant activity in pediatric pulmonary hypertension. Pediatr Pulmonol. 2019 Jan;54(1):66-72. doi: 10.1002/ppul.24190. Epub 2018 Nov 28. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Curator comments
Treprostinil is primarily metabolized by CYP2C8.
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. FDA Approved Drug Products: TYVASO (treprostinil) inhalation solution, for oral inhalation use [Link]
  2. FDA Approved Drug Products: REMODULIN (treprostinil) injection, for subcutaneous or intravenous use [Link]
  3. FDA Approved Drug Products: ORENITRAM (treprostinil) extended-release tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Gotzkowsky SK, Dingemanse J, Lai A, Mottola D, Laliberte K: Lack of a pharmacokinetic interaction between oral treprostinil and bosentan in healthy adult volunteers. J Clin Pharmacol. 2010 Jul;50(7):829-34. doi: 10.1177/0091270009351173. Epub 2010 Feb 4. [Article]
  2. FDA Approved Drug Products: ORENITRAM (treprostinil) extended-release tablets, for oral use [Link]

Drug created at June 13, 2005 13:24 / Updated at August 12, 2022 17:06