Off-label use of treprostinil in adult patients in clinical cases

Table 1 Treprostinil mechanisms of action

Number	Effect
1	Vasodilation
2	Inhibition of platelets aggregation
3	Inhibition of platelets adherence
4	Reversion of pulmonary remodelling
5	Decrease of muscle cell proliferation rate
6	Regulation of vascular homeostasis
7	Attenuation of inflammatory response
8	Upregulation of apoptosis rate
9	Elevation of ATP production
10	Preservation of mitochondrial biogenesis

Table 2 World Health Classification of pulmonary hypertension and treprostinil indications

Group	Indication	Treprostinil use status
Group 1	Pulmonary arterial hypertension	Approved
Group 2	Pulmonary hypertension due to left heart disease	Has not been tested
Group 3	Pulmonary hypertension associated with lung disorders	Off-label use
Group 4	Pulmonary hypertension due to pulmonary artery obstructions	Off-label use
Group 5	Miscellaneous (unclear or multifactorial mechanisms)	Has not been tested

Table 3 Proposed treprostinil dosing schemes in selected diseases according to current data, which demonstrated the efficacy of treprostinil

Ref.	Type of study	Disease	Number of patients	Dosage	Follow-up	Results
Engel et al[10], 2005	Case report	Digital necrosis in systemic sclerosis	1	15 ng/kg/min subcutaneous infusion for 16 weeks	1 year	Healing of lesions
Chung et al[11], 2006	Open-label, single center trial	Digital ulcers in systemic sclerosis	12	15 ng/kg/min subcutaneous infusion for 12 weeks	8 weeks	Resolution of baseline digital ulcers
Shah et al[12], 2013	Open-label, dual center, phase I pharmacokinetic study	Digital ulcers secondary to scleroderma	20	4 mg BID per os for 8 weeks	8 weeks	Increase in digital perfusion
Hellmann et al[13], 2015	Double-blind randomized pharmacology study	Diabetic ulcers	24	0,1 mg/mL solution for iontophoresis	-	Increase in microvascular blood flux in the malleolus area
Roustit et al[14], 2014	Randomized controlled trial	Digital ulcers in systemic sclerosis	12	Iontophoresis at 240 mC/cm2	-	Increase in digital skin perfusion
Gaillard-Bigot et al[15], 2016	Prospective study	Digital ulcers in systemic sclerosis	11	Simultaneous double-blinded iontophoresis (0.1 mg/mL)	-	Increase in skin blood flow
Berman et al[21], 2006	Open-label, single-center pilot study	Critical limb ischemia	10	15 ng/kg/min subcutaneous infusion	12 weeks	Reduction in ischemic rest pain
Almazroo O et al[28], 2021	Prospective, single-center, non-randomized, interventional study	Ischemia – reperfusion injury in adult liver transplantation	35	2.5, 5, 7.5 ng/kg/min in continuous IV infusion for 120 hours	180 days	No primary graft non-function, minimized need for ventilation support, reduced hospitalization time, 100% graft and patient survival
Nathan et al[36], 2021	Multicenter, randomized, double-blind, placebo-controlled trial	Pulmonary hypertension due to interstitial lung disease	326	72 μg inhaled treprostinil	16 weeks	Improvement of exercise capacity
Sadushi-Kolici and Lang[41], 2019	Multicenter, randomised, double-blind controlled trial	Chronic thromboembolic pulmonary hypertension	105	3 ng/kg/min or 30 ng/kg/min subcoutaneous treprostinil for 12 weeks	24 weeks	Improvement of exercise capacity
Skoro-Sajer et al, 2007[42]	Open-label uncontrolled study		25	2 ng/kg/minute continuous subcutaneous infusion for 12 weeks	24 ± 18 months	Improvement of exercise capacity, haemodynamics and survival
Nathan et al, 2022[46]	2 randomised, double-blind placebo-controlled, phase 3 studies	Idiopathic pulmonary fibrosis	792	72 μg inhaled treprostinil	52 weeks	Ongoing study