Therapeutic Potential of Treprostinil Inhalation Powder for Patients with Pulmonary Arterial Hypertension: Evidence to Date

Figures & data

Table 1 Advantages and Disadvantages of Prostacyclin Formulations

Delivery Method	Advantages	Disadvantages
Oral	Convenient route of administration Approved as add-on therapy for patients with PAH WHO FC II and III Formulations with long T1/2 (selexipag) have twice-daily dosing with improved adherence.	Systemic class adverse effects, including headache, nausea, jaw pain, are common and typically mild to moderate Selexipag requires dose adjustment for hepatic clearance
Inhaled	Theoretically improved drug delivery to areas experiencing VQ mismatch Reduced risk of systemic class side effects (hypotension, headache, nausea, jaw pain) Decreased reliance on kidney or liver clearance due to direct drug delivery	Variable half-life with current formulations necessitates dosing from four to nine times daily Increased irritant effects on airways with resultant cough and chest pain Patient education on self-administration needed for both nebulized and DPI formulations Current formulations are very costly Long-term outcomes not well established
Parenteral	Continuous IV formulations with short and long-term showed significant improvements in symptoms, functional capacity/walk distance Only form with demonstrated mortality benefit Fewer peaks and troughs allow for faster titration Approved for patients with PAH WHO FC III and IV	Short t1/2 requires continuous administration with tunneled central line or subcutaneously, with strict hygiene requirements Requires extensive patient and caregiver education to become facile with equipment Increased risk related to thrombosis and CVC infections Significant severe rebound PAH if promptly discontinued Subcutaneous forms associated with injection site pain and rarely skin necrosis

Figure 1 (A and B) Tyvaso delivery devices. Views of the Tyvaso nebulizer device and Tyvaso direct powder inhaler (DPI) device, with sizes to scale. Drug ampules(in envelope) are used with the nebulizer device, while cartridges (here, a light green 64 mcg dose cartridge) are used with the DPI device.

Table 2 Approved and Experimental Formulations of Inhaled Treprostinil

Formulation	Dosing	Key Trials	FDA Approval
Treprostinil nebulizer (Tyvaso)	3 breaths (18 mcg) four times daily, increasing by 3 breaths every 1–2 weeks to target dose of 9–12 breaths four times daily	Inhaled treprostinil in pulmonary hypertension due to interstitial lung disease (INCREASE)^Citation7	WHO Group I (PAH) (October 2017) WHO Group III (PH-ILD) (April 2021)
Treprostinil dry powder inhaler (Tyvaso DPI)	1 breath four times daily Cartridges available in 18, 32, and 64 mcg; 80 mcg dosing uses two cartridges (64 + 18 mcg)	BREEZE: Open‐label clinical study to evaluate the safety and tolerability of treprostinil inhalation powder as Tyvaso DPI™ in patients with pulmonary arterial hypertension^Citation31	WHO Group I (PAH) WHO Group III (PH-ILD) (both May 2022)
Treprostinil palmitil inhalation powder (TPIP)	1 administration daily starting at 80 mcg Uptitration during study to highest tolerated dose up to 640 mcg (study schedule)	A Study to Evaluate the Efficacy, Safety and Pharmacokinetics of Treprostinil Palmitil Inhalation Powder in Participants With Pulmonary Arterial Hypertension (NCT05147805, Phase 2b)	None
Treprostinil inhalation powder (Yutrepia)	2 breaths per capsule four times daily Initial dosing of 26.5 mcg; maximum dose not established	INSPIRE: Safety and tolerability of inhaled Yutrepia (treprostinil) in pulmonary arterial hypertension (PAH) (Phase 3)^Citation33	None

Waxman A, Restrepo-Jaramillo R, Thenappan T, et al. Inhaled treprostinil in pulmonary hypertension due to interstitial lung disease. N Engl J Med. 2021;384(4):325–334. doi:10.1056/NEJMoa2008470

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Spikes LA, Bajwa AA, Burger CD, et al. BREEZE: open-label clinical study to evaluate the safety and tolerability of treprostinil inhalation powder as Tyvaso DPI in patients with pulmonary arterial hypertension. Pulm Circ. 2022;12(2):e12063. doi:10.1002/pul2.12063

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Hill NS, Feldman JP, Sahay S, et al. INSPIRE: safety and tolerability of inhaled Yutrepia (treprostinil) in pulmonary arterial hypertension (PAH). Pulm Circ. 2022;12(3):e12119. doi:10.1002/pul2.12119

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