Treprostinil

Introduction Overview

Generic Name

treprostinil

Brand Name

Yutrepia

Dosage Form

inhalation powder contained in capsules for oral inhalation

Drug Class

Agents for pulmonary hypertension

Pharmacokinetics

Absorption:
Yutrepia contains treprostinil delivered as an oral inhalation powder. Following inhaled administration of Yutrepia, treprostinil is rapidly absorbed, achieving a median time to maximum plasma concentration (Tmax) of approximately 0.13 hours (8 minutes). Systemic exposure, including peak plasma concentration (Cmax) and area under the curve (AUC), is proportional to the inhaled doses ranging from 25 mcg to 150 mcg. For example, a single inhaled dose of 79.5 mcg results in a mean Cmax of 1.48 ng/mL and a mean AUC0-inf of 1.04 hr·ng/mL. The inhalation device delivers a consistent delivered dose, though patient factors such as inspiratory flow may influence lung deposition.

Distribution:
Treprostinil exhibits substantial plasma protein binding, approximately 91% over a concentration range of 330-10,000 ng/mL, primarily to albumin. It distributes into pulmonary and systemic arterial vascular beds to exert its pharmacological effects. The volume of distribution after inhalation has not been explicitly reported but is consistent with distribution specifically targeting lung vasculature. No significant binding to red blood cells has been documented. Treprostinil does not noticeably distribute into adipose tissue, being more limited to plasma and vascular compartments.

Metabolism:
Treprostinil is extensively metabolized predominantly by the liver. The primary metabolic pathway is via CYP2C8 mediated oxidation, yielding five main metabolites, four of which result from oxidation of the 3-hydroxyloctyl side chain, and a fifth is a glucuronide conjugate. These metabolites are pharmacologically inactive. Human hepatic microsome studies indicate minimal inhibitory or inductive effects of treprostinil on major CYP enzymes including CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A, suggesting a low potential for metabolism-related drug–drug interactions.

Elimination:
The elimination of treprostinil following inhaled administration is defined by a monophasic decay with a half-life of approximately 30 minutes. Excretion occurs mainly via metabolism followed by renal elimination of metabolites; only about 4% of subcutaneously administered treprostinil is excreted unchanged in urine. Approximately 79% and 13% of the dose is recovered in urine and feces, respectively, over 10 days. The elimination half-life and clearance are notably prolonged in patients with hepatic impairment due to reduced metabolic capacity, necessitating careful dose titration in these populations. Renal impairment does not significantly alter systemic exposure to treprostinil, and no dose adjustments are required in renal insufficiency. Treprostinil is not cleared by dialysis.

Dosage Forms

Available Dosage Forms:
Yutrepia is available as an inhalation powder contained within gelatin capsules intended for oral inhalation only via a specific capsule-based dry powder inhaler device. The capsules contain white to off-white treprostinil sodium powder along with excipients including L-leucine, polysorbate 80, sodium chloride, sodium citrate, and trehalose.

Capsule strengths include:
- 26.5 mcg (opaque yellow cap, clear body capsule, imprinted with “LIQUIDIA 26.5” in black ink)
- 53 mcg (opaque green cap, clear body capsule, imprinted with “LIQUIDIA 53” in white ink)
- 79.5 mcg (opaque blue cap, clear body capsule, imprinted with “LIQUIDIA 79.5” in white ink)
- 106 mcg (opaque purple cap, clear body capsule, imprinted with “LIQUIDIA 106” in white ink)

Each capsule contains a specified mcg dose of treprostinil; the amount delivered to the lungs varies by dose (e.g., 15.1 mcg delivered lung dose from a 26.5 mcg capsule).

Dosages for Adults and Adolescents:
Yutrepia is administered by oral inhalation only; capsules must not be swallowed. The standard dosing frequency is 3 to 5 times per day. Each capsule’s contents are inhaled typically in two breaths.

- Initiation in treprostinil-naïve adults begins at 26.5 mcg inhaled 3 to 5 times daily.
- Dose titration is recommended weekly in increments of 26.5 mcg per dose as tolerated.
- Target maintenance doses generally range between 79.5 mcg to 106 mcg inhaled four times daily.
- Patients transitioning from treprostinil inhalation solution (Tyvaso) have specified dose equivalents based on their prior inhalation breaths; for example, ≤5 breaths Tyvaso corresponds to 26.5 mcg Yutrepia, 6–8 breaths to 53 mcg, up to ≥18 breaths corresponding to doses as high as 159 mcg.
- The maximum studied dose is 848 mcg daily; doses above this have not been evaluated.

Specific Patient Populations:
- Patients with hepatic insufficiency should be dosed cautiously due to reduced clearance and increased systemic exposure; slow uptitration is emphasized.
- No dose adjustment is required for renal impairment.
- Safety and efficacy in pediatric patients have not been established.
- The elderly may require cautious dose selection because of increased potential for hepatic, renal, or cardiac dysfunction.

Inhaler Device and Handling:
Yutrepia capsules are to be used exclusively with the proprietary dry powder inhaler device supplied. The inhaler is reusable for up to 7 days or 56 actuations, after which it should be discarded. Capsules must remain sealed in blister packs until use to preserve drug stability and moisture protection. Each capsule must be inhaled within five minutes of removal from the blister to ensure full dose delivery.

Dosing Combinations:
For prescribed doses exceeding 106 mcg, two capsules of specified strengths are inhaled sequentially, following the recommended dosing chart to achieve accurate dosing. Capsules from different strength cartons may be combined if clinically indicated, always inhaling one capsule at a time to ensure proper delivery and patient tolerance.

Mechanism Of Action

Yutrepia’s active ingredient, treprostinil, is a stable prostacyclin (PGI2) analogue that mimics endogenous prostacyclin effects. The primary mechanism involves the direct vasodilation of both pulmonary and systemic arterial vascular beds through activation of prostacyclin (IP) receptors located on vascular smooth muscle cells. This binding increases intracellular cyclic adenosine monophosphate (cAMP) levels, leading to smooth muscle relaxation and vasodilation.

In addition to vasodilation, treprostinil inhibits platelet aggregation by modulating platelet function through IP receptor activation on platelets, thereby diminishing thrombosis risk within the pulmonary circulation. This antiplatelet effect contributes to improved blood flow and reduced vascular obstruction in pulmonary arterial hypertension.

At the cellular level, treprostinil's activation of cAMP-dependent pathways also confers antiproliferative and anti-inflammatory effects on vascular smooth muscle cells, potentially preventing or attenuating vascular remodeling and progression of pulmonary hypertension. Preclinical studies demonstrate dose-dependent negative inotropic (contractility) and lusitropic (relaxation) effects on the heart, although these are modest and clinically manageable.

Compared to other prostacyclin analogues like epoprostenol, treprostinil has a longer half-life and increased stability, allowing for flexible routes of administration including inhalation. Inhaled treprostinil delivers targeted therapy to the pulmonary vasculature, minimizing systemic adverse effects and improving patient convenience. Clinical studies support its efficacy in improving exercise capacity and hemodynamics in pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease.

Ongoing research continues to elucidate treprostinil’s molecular modulation of endothelial function and vascular remodeling, with emerging data explored to optimize dosing strategies and combination therapies with endothelin receptor antagonists and phosphodiesterase type 5 inhibitors for enhanced clinical outcomes.

Pharmacological Actions

Direct vasodilation of pulmonary and systemic arterial vascular beds reducing pulmonary vascular resistance.
Inhibition of platelet aggregation reducing thrombosis within pulmonary circulation.
Increase in intracellular cAMP in vascular smooth muscle cells leading to smooth muscle relaxation.
Negative inotropic and lusitropic effects on cardiac muscle observed in dose-dependent fashion.
Antiproliferative effects on vascular smooth muscle that may attenuate vascular remodeling.
Improvement in cardiac output and stroke volume by reducing right and left ventricular afterload.
Tachycardia as a pharmacodynamic response to vasodilation.
No significant impact on cardiac conduction observed in clinical trials.
Dose-proportional systemic exposure following inhalation allowing predictable titration.
Does not significantly inhibit or induce cytochrome P450 enzymes, minimizing drug–drug interactions.
Reduces exercise limitation in pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease.

Therapeutic Or Clinical Uses

Treatment of pulmonary arterial hypertension (PAH; WHO Group 1) to improve exercise capacity in patients primarily with NYHA Functional Class III symptoms.
Management of pulmonary hypertension associated with interstitial lung disease (PH-ILD; WHO Group 3) to improve exercise ability.
Adjunctive therapy in combination with endothelin receptor antagonists (e.g., bosentan) or phosphodiesterase type 5 inhibitors (e.g., sildenafil) in PAH.
Use in idiopathic or heritable PAH and PAH associated with connective tissue diseases.
Improvement of 6-minute walk distance as a measure of functional capacity in patients with PAH and PH-ILD.
Reduction in clinical worsening events including hospitalization in PH-ILD clinical trial data.
Improvement of hemodynamics through pulmonary vasodilation.
Treatment option for patients transitioning from treprostinil inhalation solution to a dry powder inhalation system.
Facilitates outpatient management of pulmonary hypertension with a convenient inhaled formulation.
Potential use in broader pulmonary hypertension etiologies pending further research.
Option for patients unable or unwilling to use continuous infusion prostacyclin therapies.

Side Or Adverse Effects

Cough occurring in approximately 27-55% of patients during clinical studies.
Headache reported in 25-27% of treated individuals.
Throat irritation affecting 9-21% of patients receiving therapy.
Dizziness experienced by 11% of patients.
Diarrhea seen in up to 12% of patients in clinical trials.
Chest discomfort reported by 8-9% of patients.
Nausea present in 7-8% of patients.
Dyspnea in about 5-6% of subjects.
Flushing occurring in up to 8% of treated patients.
Oropharyngeal pain reported in 2-6% of individuals.
Symptomatic hypotension due to systemic vasodilation, particularly in patients with low baseline blood pressure.
Increased risk of bleeding due to inhibition of platelet aggregation.
Bronchospasm, especially in patients with reactive airway diseases such as asthma or COPD.
Potential angioedema identified in post-marketing experience.
General overdose symptoms may include flushing, headache, hypotension, nausea, vomiting, and diarrhea.
Local irritation related to inhalation powder particles.

Precautions

Monitor blood pressure closely to detect and manage symptomatic hypotension.
Use with caution in patients with bleeding diatheses or concurrent anticoagulant therapy due to increased bleeding risk.
Patients with hyperreactive airway diseases (e.g., asthma, COPD) should be stabilized prior to initiation due to bronchospasm risk.
Dose adjustments required if concomitant CYP2C8 inhibitors (e.g., gemfibrozil) or inducers (e.g., rifampin) are started or stopped, given effect on treprostinil exposure.
Educate patients on proper inhalation technique to ensure full dose delivery.
Capsules must not be swallowed; they are for inhalation only.
Store capsules in blister packs until immediately before use to prevent moisture degradation.
Discard inhaler device after 7 days or 56 actuations to maintain drug delivery consistency.
Avoid sudden discontinuation to prevent clinical deterioration.
Monitor for hypotension and signs of bleeding especially during dose titration.
Exercise caution in elderly patients who may have decreased hepatic or renal function.
Slow titration is advised in patients with hepatic insufficiency to avoid excessive drug exposure.
Pregnant women should be counseled regarding limited safety data and potential disease-associated risks.
Instruct patients to rinse skin and eyes immediately if capsule powder contacts these areas.
Advise patients to have back-up inhaler equipment available to avoid treatment interruption.

Warnings

Risk of symptomatic hypotension due to vasodilation necessitates monitoring of systemic arterial pressure.
Risk of bleeding exists because treprostinil inhibits platelet aggregation; bleeding events may be severe.
Dosage adjustments may be necessary with drugs that alter CYP2C8 activity as they impact treprostinil systemic levels.
Potential for bronchospasm upon inhalation; patients with asthma, COPD, or bronchial hyperreactivity are at increased risk.
No known absolute contraindications identified.
Overdosage may lead to flushing, headache, hypotension, nausea, vomiting, and diarrhea requiring supportive care.
Inhaled formulation not to be swallowed to avoid unintended systemic dosing and adverse effects.
Inhaler device must be properly handled; use of damaged or expired capsules or inhalers may reduce efficacy or safety.
Pregnancy-associated risks due to underlying PAH disease necessitate careful risk versus benefit assessment.
Risk of angioedema reported in post-marketing surveillance.
Patients should be adequately trained in inhaler use to avoid dosing errors.

Contraindication

No known contraindications have been identified for Yutrepia (treprostinil inhalation powder).

Drug Interactions

Co-administration with CYP2C8 inhibitors such as gemfibrozil results in increased treprostinil exposure, elevating the risk of adverse reactions.
Use with CYP2C8 inducers like rifampin decreases treprostinil exposure and may reduce clinical efficacy.
Treprostinil does not inhibit or induce major CYP enzymes including CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A.
Drug interaction studies suggest no significant pharmacokinetic or pharmacodynamic interaction with warfarin.
No clinically significant interactions observed with acetaminophen or fluconazole in healthy volunteers.
Treprostinil does not affect the pharmacokinetics of R- or S-warfarin or the international normalized ratio (INR).
Careful monitoring is advised when adding or withdrawing other vasodilators or antiplatelet agents.
Caution with concurrent anticoagulants or antiplatelet drugs due to additive bleeding risk.
Potential interactions with other pulmonary hypertension treatments (e.g., bosentan, sildenafil) have been described but are generally well tolerated.
No reported interaction with phosphodiesterase-5 inhibitors but clinical monitoring advised.
No known significant interactions with commonly used cardiovascular or respiratory drugs.
Dose adjustments may be required based on clinical response and side effect profile when used in combination therapy.
Patients should inform healthcare providers about all concomitant medications including over-the-counter and supplements.

Preparations Of The Drug

Yutrepia is supplied as dry powder inhalation capsules containing treprostinil sodium powder with inactive ingredients: L-leucine, polysorbate 80, sodium chloride, sodium citrate, and trehalose.
Available capsule strengths: 26.5 mcg (yellow cap), 53 mcg (green cap), 79.5 mcg (blue cap), and 106 mcg (purple cap).
Each capsule is contained in a blister pack with an integrated desiccant strip to protect from moisture.
The drug is administered exclusively via a proprietary dry powder inhaler device included with the packaging.
Packaging includes cartons each containing 28 capsules (7 blister cards of 4 capsules each), one inhaler device, and seven single-use cleaning brushes.
The inhaler device is designed for one-week use or up to 56 actuations, after which it must be discarded.
Storage conditions: store capsules and inhaler at controlled room temperature 20°C to 25°C (68°F to 77°F) with allowed excursions between 15°C to 30°C (59°F to 86°F).
Keep capsules sealed in blister cards until immediately prior to use to maintain potency and stability.
Do not wash or wet the inhaler device; keep dry and clean by wiping and using the provided cleaning brush daily.
Capsules must be inhaled within 5 minutes of removal from the blister pack to ensure full dose delivery.
Dispose of used capsules in household trash; inhaler device disposal advised after one week of use.
Instructions for use include detailed steps for inhaler preparation, capsule loading, puncturing, inhalation technique, and cleaning.
Prescribed regimens may require inhalation of one or more capsules per dose, inhaling each capsule twice to ensure complete drug administration.
Capsules are for inhalation use only and must not be swallowed.
Patient counseling and training on device use and maintenance are essential for treatment efficacy and safety.