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

Abstract

Treprostinil is a relatively new tricyclic prostacyclin analog with a stable structure, extended half-life and improved potency. Currently, treprostinil is indicated by the Food and Drug Administration in the United States for the treatment of pulmonary arterial hypertension (group 1 in the pulmonary hypertension classification of the World Health Organization). It has a potent vasodilating effect along with the inhibition of platelet aggregation and the attenuation of the inflammatory response in pulmonary and systemic circulation. It is available in the following formulations: Subcutaneous, intravenous, inhaled and oral. Although unknown to many clinicians, several encouraging reports of off-label treprostinil use in the adult population suggest its potential effectiveness in other clinical conditions. Currently under investigation are digital ischemia secondary to systemic sclerosis, chronic limb ischemia, hepatic ischemia-reperfusion injury and group 3 and 4 pulmonary hypertension. Based on review and analysis of the available literature, this article provides a thorough update on the off-label use of treprostinil in adult patients.

Key Words: Treprostinil; Off-label use; Pulmonary hypertension; Digital ischemia; Chronic limb ischemia; Hepatic ischemia–reperfusion injury

Core Tip: Treprostinil is a synthetic prostacyclin analog with a stable structure that is currently used for the treatment of pulmonary arterial hypertension. By way of vasodilation and the inhibition of platelet aggregation, treprostinil increases the blood supply in pulmonary circulation and reduces the cardiac workload. In addition to its main indication, several positive reports of off-label treprostinil use in the adult population indicate its benefit in other clinical conditions. Hepatic ischemia–reperfusion injury, chronic limb ischemia, digital ischemia and group 3 and 4 pulmonary hypertension are currently under study as possible indications for treprostinil use outside its approved labeling.

INTRODUCTION

Treprostinil is a prostacyclin (PGI₂) analog primarily approved by the Food and Drug Administration (FDA) in the United States for the treatment of pulmonary arterial hypertension (PAH). PAH is a subtype of pulmonary hypertension in which pulmonary artery remodeling results in right heart failure and death[1]. In addition to several supportive methods to offer symptomatic relief, several medical therapeutic options that target mainly endothelin receptors, nitric oxide–guanylyl cyclase and PGI₂ signaling pathways exist. Treprostinil is a synthetic, chemically stable PGI₂ analog with potent vasodilating and antithrombotic effects. In the pulmonary circulatory system, it causes relaxation of the pulmonary vasculature, reduces platelet aggregation, reverses pulmonary artery remodeling and decreases the proliferation rate of muscle cells through the activation of peroxisome proliferator-activated receptor γ[2]. Treprostinil is also known for its anti-inflammatory effect while reducing cytokine release and lipid peroxidation[3]. The main biochemical interactions of treprostinil are summarized in Table 1.

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

Treprostinil is available via four possible routes of administration: Intravenous, subcutaneous, oral and inhaled. In vitro studies have shown high affinity for the prostaglandin DP₁, EP₂, and IP receptors, all of which activate the intracellular cyclic adenosine monophosphate signaling pathway[4,5]. Treprostinil has shown clinical effectiveness in the treatment of PAH by delaying disease progression. The simplified mechanisms of action of treprostinil are shown in Figure 1. However, several other clinical conditions appear to benefit from treprostinil administration under certain circumstances. In this mini-review, we discuss the off-label uses of treprostinil based on its mechanisms of action and the results of clinical studies.

Figure 1 Simplified mechanisms of actions of treprostinil. IP: Prostacyclin.

SYSTEMIC SCLEROSIS AND DIGITAL ISCHEMIA

Digital ischemia is a serious complication of systemic sclerosis, resulting in significant morbidity and gangrene, necessitating amputation in some cases. The activation of innate immune responses, progressive fibrosis and the development of vasculopathy constitute some of the causative mechanisms, but the pathogenesis of systemic sclerosis is not completely understood[6]. Peripheral altered vascular reactivity presents as a common evolution of the underlying disease, resulting in Raynaud’s phenomenon. At the early stages of the disease, Raynaud’s phenomenon is characterized by pallor and cyanosis followed by hyperemia of the digits due to symmetrical transient vascular events triggered by exposure to low temperature or emotional stress. Recurrent episodes of digital ischemia can result in digital ulcers with the loss of continuous epithelial coverage. However, a prolonged reduction in digital perfusion can cause critical damage to tissues with impaired endurance[7,8]. The etiology of the ischemic events includes a combination of intimal hyperplasia, episodes of vasospasm and in situ thrombosis[9]. Among other therapeutic options to enhance peripheral microcirculation, PGI₂ analogs have improved microvascular arterial flow and velocity, remission of digital ulcers and attenuation of ischemic pain. Treprostinil has been used in a small population of patients with systemic sclerosis to improve peripheral blood flow and prevent or heal digital ulcers. Continuous subcutaneous treprostinil infusion resulted in complete resolution of baseline digital ulcers in most of these patients. Additionally, no new lesions were observed during continuous therapy, suggesting the important role of treprostinil in preventing the development of new ulcers. However, injection site reactions and diarrhea were observed in some patients, resulting in drug discontinuation in 5 patients. The high rate of adverse events suggests that the use of treprostinil in particular formulations is challenging and indicates an urgent need for larger studies to determine the route, length and dose of therapy[10,11]. The administration of treprostinil as an oral sustained-release osmotic tablet (treprostinil diethanolamine) was associated with improved digital perfusion and mild or moderate adverse events possibly related to the study drug following dose escalation. In detail, the plasma drug concentrations of oral doses were similar to those reported during continuous infusion. Moreover, significant improvement in perfusion was observed after treprostinil administration, as assessed by laser Doppler imaging. Finally, digital skin temperature was positively associated with the drug plasma concentration[12].

Treprostinil administration via cathodal iontophoresis enables local noninvasive transdermal delivery of the drug, avoiding systemic side effects (Figure 2). Recent studies have demonstrated improvements in skin vascular blood flux, with an extended duration of the effect even after the procedure and a very low rate of digital ulcer recurrence. Noninvasive laser speckle contrast imaging was used to determine the effectiveness of local therapy, but no systemic or local side effects were described[13-15]. Overall, recent reports have shown favorable effects of locally delivered treprostinil in patients with systemic sclerosis and digital ischemia, but larger clinical studies are needed.

Figure 2 Schematic representation of iontophoretic treprostinil delivery.

CHRONIC LIMB ISCHEMIA

Chronic limb-threatening ischemia is a severe peripheral vascular disease caused by progressive occlusion of the arterial branches of the lower extremities. The development of atherosclerotic plaques leads to advanced arterial stenosis with a reduced blood supply, hypoxia, reactive oxygen species formation, oxidative stress, arteriolar vasospasm, platelet aggregation, leucocyte activation and inflammation, microthrombosis, microcirculatory disfunction and muscle cell necrosis[16]. In the later stages of the disease, the degeneration of blood vessels leads to the formation of nonhealing ulcers, necrotic lesions and/or gangrene[17,18]. Bypass surgical techniques and endovascular procedures are the gold standard strategies that aim to restore the blood supply, but not all patients are suitable for these therapies due to their comorbidities or advanced age. Therefore, a number of pharmacological agents have been used in patients with critical limb ischemia and microcirculatory dysfunction who do not meet the criteria for revascularization[19].

During the past thirty years, PGI₂ analogs have been studied for the management of patients in the early stages of peripheral arterial disease and critical limb ischemia[20]. Based on acknowledged mechanisms of action and previous reports, Berman et al[21] conducted an open-label, single-center pilot study to assess the safety and effectiveness of treprostinil administration in patients with critical limb ischemia and no planned revascularization. Each patient with Fontaine stage III to IV (Rutherford class 4-6) peripheral arterial disease received an escalated dose of treprostinil via continuous subcutaneous infusion for 12 weeks. All patients reported improvement in pain, while a positive effect on ischemic lesion healing was observed. Moreover, treprostinil is considered a safe and well-tolerated pharmacological agent in these particular populations.

HEPATIC ISCHEMIA–REPERFUSION INJURY

Hepatic ischemia–reperfusion injury is a common pathophysiological event that usually follows major surgical procedures for liver and liver transplantation. Severe inflammatory reactions and oxidative stress during reperfusion of ischemic hepatic tissue lead to extreme tissue damage and cell death with widespread local and systemic consequences[22-24]. The molecular mechanisms responsible for cell damage are exceedingly complicated; therefore, various types of pharmacological interventions and antioxidant agents have been used to intervene in the different phases of hepatic ischemia–reperfusion injury to suppress this phenomenon[25].

A shortage of organs suitable for transplantation has resulted in a major organ shortage crisis and necessitated the use of extended-criteria donor livers, which are more susceptible to ischemia–reperfusion injury[26]. For nearly forty years, numerous studies have investigated the advantages of PGI₂ analog administration in hepatic ischemia–reperfusion injury, with rather encouraging results.

In an orthotopic rat liver transplant model, treprostinil administration protected liver grafts from ischemia–reperfusion injury by restoring energy levels, reducing platelet aggregation and preserving the blood supply[27]. Treprostinil has also been used in adult liver transplant patients in a prospective, single-center, nonrandomized, interventional study to assess the safety and effectiveness of the study drug in the aforementioned population. Patients who underwent liver transplantation received treprostinil at a dose of 5 ng/kg/minute for 2 days or 2.5, 5, or 7.5 ng/ minute/kg for 5 days as a continuous infusion. With no reported cases of primary graft nonfunction, treprostinil infusion up to 5 ng/ minute/kg for 120 hours was safe and well tolerated. Furthermore, the authors reported a minimized need for ventilation support, reduced hospitalization time, enhanced hepatobiliary excretory function and 100% graft and patient survival[28,29].

OTHER SUBTYPES OF PULMONARY HYPERTENSION

Pulmonary hypertension in interstitial lung disease

Interstitial lung disease is a heterogeneous group of diffuse parenchymal lung disorders that are characterized primarily by fibrosis of the lung parenchyma. Up to 86% of patients with interstitial lung disease have been shown to develop pulmonary hypertension with a higher demand for supplementary oxygen, decreased quality of life and worse outcomes[30,31]. In the pulmonary hypertension classification of the World Health Organization (WHO), pulmonary hypertension due to lung disease is classified into group 3 (Table 2). Regardless of the widespread occurrence worldwide and the progressive nature of the disease, there are currently no approved therapies for these patients.

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

Based on data that PGI₂ analogs improve exercise capacity in patients with PAH, vasodilator therapies have been used to treat group 3 patients[32-34]. Although not originally approved for this purpose, treprostinil has shown efficacy in treating pulmonary hypertension associated with interstitial lung disease. Patients treated with inhaled treprostinil had significant improvements in exercise capacity and increased forced vital capacity at 16 weeks[35-37]. The exacerbation of the underlying lung disease rate was significantly lower in the treprostinil group than in the placebo group, whereas no statistically significant differences in serious adverse events were detected between the drug and placebo groups.

Chronic thromboembolic pulmonary hypertension

The pulmonary hypertension classification of the WHO categorizes chronic thromboembolic pulmonary hypertension (CTEPH) into group 4. Chronic obstruction of the pulmonary vascular bed by nonresolving organized thromboemboli causes increased resistance in pulmonary circulation, right ventricular overload and progressive right heart failure[38]. The thromboembolic material remains resistant for at least three months of uninterrupted anticoagulation therapy. To this degree, pulmonary endarterectomy is the treatment of choice for these patients; however, not all individuals are ideal candidates for surgical intervention, mainly due to significant distal small vessel disease[39]. Although riociguat is the only pharmacological agent approved for treating CTEPH, treprostinil has been explored as an alternative therapeutic option to improve symptoms in inoperable patients or those with residual postoperative disease[40,41].

Published data on the effects of long-term treprostinil therapy (> 2 years) demonstrated that long-term treatment ameliorated hemodynamic measurements and improved survival[42]. Patients with inoperable CTEPH (distal small vessel disease, resistant or recurrent pulmonary hypertension after endarterectomy, severe comorbidities) and typical abnormal pulmonary angiography findings received continuous subcutaneous treprostinil at an adjusted dose with the use of a positive pressure microinfusion pump. Exercise capacity was significantly improved in patients treated with treprostinil. Moreover, B-type natriuretic peptide plasma levels, pulmonary resistance, cardiac output and right ventricular end-diastolic pressure were also improved. Although the mean pulmonary arterial pressure was reduced, the difference was not statistically significant. The study also confirmed the successful management of local pain at the infusion site and maintained efficacy over an extended period of time.

Idiopathic pulmonary fibrosis with pulmonary hypertension

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by progressive lung fibrosis, ongoing respiratory failure and premature mortality[43]. Pulmonary hypertension is common in patients with IPF and is classified as Group 3 according to the WHO classification[44]. As mentioned above, there are limited pharmacological therapeutic options available for these patients, but lung transplantation constitutes the optimal treatment[45].

An inhaled treprostinil formulation has been considered to improve symptoms and exercise capacity in patients with pulmonary hypertension secondary to IPF. The TETON program, an ongoing phase III clinical trial, assesses the long-term safety and tolerability of inhaled treprostinil in patients with a diagnosis of IPF[46]. Based on the combination of preclinical evidence of treprostinil antifibrotic activity and results from previous studies, the TETON program aims to study changes in absolute forced vital capacity and overall survival at week 52 in IPF patients who received inhaled treprostinil.

STRATEGIES FOR FUTURE STUDIES ON TREPROSTINIL OFF-LABEL USE

A number of reports have investigated the use of treprostinil beyond its approved labeling, but clinical evidence remains limited. Treprostinil has a known side effect profile consisting of coughing, headache, nausea, diarrhea, hypotension, flushing, jaw pain and extremity pain, which may be hard to manage in an off-label context[47]. Furthermore, prescribing high-cost treatment involves negotiating a complex regulatory framework, as its unapproved administration is not supported by the latest clinical guidelines[48]. The lack of established protocols may also be challenging, as interruptions in treprostinil therapy or difficulty in reaching the optimal dose can lead to negative outcomes[49]. The proposed treprostinil dosing schemes for selected diseases according to current data, which demonstrate the efficacy of treprostinil, are shown in Table 3. The use of treprostinil for other clinical conditions requires extensive research, potentially prolonged and expensive processes, without any guarantee of positive results.

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

Although treprostinil has high potential for off-label use, further research is necessary to ensure patient safety and therapeutic efficacy. Future studies should follow methodized strategies to provide scientific accuracy and clinical implementation. Preclinical studies using cellular and animal models should provide detailed information on the vasodilating, anti-inflammatory, antithrombotic and antifibrotic effects of treprostinil, along with dosing and toxicity levels. Small-scale and large-scale randomized controlled trials could determine the effectiveness of off-label treprostinil compared with standard treatment in certain groups of patients. To achieve that, approved criteria for primary and secondary outcomes should be established, such as signs of clinical improvement, reduction in inflammatory or fibrotic markers, formulation of quality-of-life scores and development of long-term disease progression markers. Overcoming the lack of scientific data, funding limitations and regulatory considerations, along with securing FDA guidance for drug repurposing, will become key to expanding treprostinil clinical applications[50].

Additionally, there are limitations regarding the off-label use of treprostinil, including its cost, the risk of complications, and the lack of standardized protocols[47-49]. Therefore, the decision to use this drug should be made based on the best possible treatment for each patient. However, this article opens new horizons for both clinical and experimental preclinical studies, which are necessary for drawing safe conclusions. The above limitations of the research should be indicated in future research studies.

CONCLUSION

Off-label treprostinil administration includes the use of the medication for medical conditions beyond its primary indication in a certain unapproved group of patients. Decision-making is often based on known pharmacological mechanisms and evidence from clinical studies. Current evidence-based indications for off-label treprostinil use are digital ischemia secondary to systemic sclerosis, chronic limb ischemia, hepatic ischemia–reperfusion injury and group 3 and 4 pulmonary hypertension. Treprostinil unapproved use provides alternative options to patients who have exhausted the standard choices of treatment. The present knowledge demonstrates the safety, efficacy and tolerability of treprostinil use. However, clinicians should consider the possibility of a favorable benefit–risk ratio for each patient separately. More clinical trials need to be conducted on larger populations to support the use of treprostinil in the discussed clinical conditions to gain approval.