Treprostinil: Mechanism of Action, Clinical, and Translational Science.
- 1Department of Pulmonary and Critical Care Medicine, Jefferson Einstein Philadelphia Hospital Pulmonary & Critical Care, Philadelphia, Pennsylvania, USA.
- 2Department of Family & Community Medicine, Jefferson Einstein Philadelphia Hospital Family & Community Medicine, Philadelphia, Pennsylvania, USA.
- 3Department of Pharmacy, Jefferson Einstein Philadelphia Hospital Pharmacy, Philadelphia, Pennsylvania, USA.
Abstract
Treprostinil is a synthetic prostacyclin analogue with a tricyclic benzindene structure that confers markedly enhanced metabolic stability relative to native prostacyclin, enabling delivery by four distinct routes-intravenous, subcutaneous, inhaled, and oral-that together constitute a mainstay of pharmacotherapy for pulmonary arterial hypertension (PAH). Herein, we review the mechanism of action, pharmacokinetic/pharmacodynamic (PK/PD) characteristics, and clinical development of treprostinil, with primary emphasis on its well-established role in PAH, including detailed dosing and PK data across all four approved routes, and secondary emphasis on its recently approved role in pulmonary hypertension associated with interstitial lung disease (PH-ILD) and its investigational, plausible-future role in idiopathic pulmonary fibrosis (IPF) without a pulmonary hypertension requirement. Treprostinil activates the Gαs-coupled prostacyclin (IP) receptor to generate a sustained nuclear cyclic adenosine monophosphate (cAMP) signal that is qualitatively distinct from earlier prostacyclin analogues, underlying both its established vasodilatory, antiproliferative, and antiplatelet effects in PAH and a mechanistic hypothesis of antifibrotic activity relevant to IPF. Treprostinil also engages the prostaglandin EP₂ and DP₁ receptors and peroxisome proliferator-activated receptors, and inhibits transforming growth factor-β (TGF-β)-driven extracellular matrix synthesis through mechanisms only partially explained by cAMP magnitude. Across the four approved routes, treprostinil exhibits route-specific pharmacokinetics-near-complete subcutaneous bioavailability with a 4-hour terminal half-life, oral bioavailability of approximately 17% with extensive first-pass CYP2C8 metabolism, and inhaled systemic bioavailability of approximately 64%-72%-that inform the distinct dosing and titration strategies detailed in this review. In a plausible, still-investigational extension of this pharmacology beyond PAH, two replicate Phase 3 trials (TETON-1 and TETON-2) have reported that inhaled treprostinil reduces the decline in forced vital capacity (FVC) and the risk of clinical worsening in patients with IPF without a pulmonary hypertension requirement. These findings support a plausible antifibrotic hypothesis pending confirmatory evidence and regulatory review; treprostinil is not currently approved for an IPF indication, and this signal should be interpreted as hypothesis-generating rather than establishing disease modification.
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BibTeX
@article{sameed2026treprostinil,
title = {{Treprostinil: Mechanism of Action, Clinical, and Translational Science.}},
author = {Muhammad Sameed and Muhammad Waleed and Veronika Colomy},
journal = {Clinical and translational science},
year = {2026},
month = nov,
doi = {10.1111/cts.70749},
url = {https://europepmc.org/article/MED/42969503},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Treprostinil: Mechanism of Action, Clinical, and Translational Science.
AU - Muhammad Sameed
AU - Muhammad Waleed
AU - Veronika Colomy
PY - 2026
DA - 2026/11/01
JO - Clinical and translational science
DO - 10.1111/cts.70749
UR - https://europepmc.org/article/MED/42969503
AB - Treprostinil is a synthetic prostacyclin analogue with a tricyclic benzindene structure that confers markedly enhanced metabolic stability relative to native prostacyclin, enabling delivery by four distinct routes-intravenous, subcutaneous, inhaled, and oral-that together constitute a mainstay of pharmacotherapy for pulmonary arterial hypertension (PAH). Herein, we review the mechanism of action, pharmacokinetic/pharmacodynamic (PK/PD) characteristics, and clinical development of treprostinil, with primary emphasis on its well-established role in PAH, including detailed dosing and PK data across all four approved routes, and secondary emphasis on its recently approved role in pulmonary hypertension associated with interstitial lung disease (PH-ILD) and its investigational, plausible-future role in idiopathic pulmonary fibrosis (IPF) without a pulmonary hypertension requirement. Treprostinil activates the Gαs-coupled prostacyclin (IP) receptor to generate a sustained nuclear cyclic adenosine monophosphate (cAMP) signal that is qualitatively distinct from earlier prostacyclin analogues, underlying both its established vasodilatory, antiproliferative, and antiplatelet effects in PAH and a mechanistic hypothesis of antifibrotic activity relevant to IPF. Treprostinil also engages the prostaglandin EP₂ and DP₁ receptors and peroxisome proliferator-activated receptors, and inhibits transforming growth factor-β (TGF-β)-driven extracellular matrix synthesis through mechanisms only partially explained by cAMP magnitude. Across the four approved routes, treprostinil exhibits route-specific pharmacokinetics-near-complete subcutaneous bioavailability with a 4-hour terminal half-life, oral bioavailability of approximately 17% with extensive first-pass CYP2C8 metabolism, and inhaled systemic bioavailability of approximately 64%-72%-that inform the distinct dosing and titration strategies detailed in this review. In a plausible, still-investigational extension of this pharmacology beyond PAH, two replicate Phase 3 trials (TETON-1 and TETON-2) have reported that inhaled treprostinil reduces the decline in forced vital capacity (FVC) and the risk of clinical worsening in patients with IPF without a pulmonary hypertension requirement. These findings support a plausible antifibrotic hypothesis pending confirmatory evidence and regulatory review; treprostinil is not currently approved for an IPF indication, and this signal should be interpreted as hypothesis-generating rather than establishing disease modification.
SN - 1752-8054
SN - 1752-8062
ER -