Uptravi Safe and Effective in Temporary Use as IV Infusion, PAH Trial Finds
Patients reported mild side effects from the switch, with the most frequent being common to both oral and intravenous delivery of Uptravi.
The study, “Temporarily switching from oral to intravenous selexipag in patients with pulmonary arterial hypertension: safety, tolerability, and pharmacokinetic results from an open-label, phase III study,” was published in the journal Respiratory Research.
Uptravi, sold by Janssen (part of Johnson & Johnson), is a selective prostacyclin receptor agonist, meaning the molecule acts like prostacyclin, a hormone that regulates blood pressure. It binds to receptors on the cells of blood vessel walls, causing the vessels to relax and expand. Uptravi was approved as an oral treatment based on positive results in the Phase 3 GRIPHON trial (NCT01106014).
Continuous use is important for maintaining treatment effectiveness in PAH, delaying disease progression. But patients hospitalized for a surgery may need to temporarily stop taking an oral therapy.
Keeping an intravenous (IV, into the vein) treatment at the same stable dose level as a patient’s oral therapy could avoid interrupting treatment and that risks that raises. It also helps to avoid the possibility of needing to readjust the oral dose or change the therapy, the researchers said.
A Phase 3 trial (NCT03187678) was conducted to assess the safety, efficacy, and pharmacokinetics of temporarily changing from oral to IV Uptravi, and then switching back to the oral formulation. (Pharmacokinetics refers to the movement of a drug into, through, and out of the body.)
The trial enrolled 20 PAH patients, ages 18 to 75 (mean age of 56.5), whose disease fell within World Health Organization functional classes (WHO FC) I–III. Most participants (80%) were women.
All underwent three consecutive treatment periods. In period one, patients were given their stable oral dose (400–1600 micrograms) in the morning and evening of the first day. Period two covered day 2 and part of day 3: patients were given an IV infusion of Uptravi, tailored to match their stable oral dose, in the morning and evening of the second day and morning of the third day. In period three, they returned on the evening of day 3 to their stable oral dose for nine days. All were then followed for safety for another 30 days.
Notably, IV doses were 12.5% higher than the matching oral dose to achieve a similar exposure to Uptravi’s active metabolite. (An active metabolite refers to the active form of a therapy after processing by the body, or the end product of metabolism.)
In addition to safety and tolerability, WHO functional status and blood pressure were also evaluated at the beginning, during, and at the end of treatment.
All patients completed the study and tolerated well the switch from oral to IV Uptravi and back, and no unexpected safety outcomes were found.
Reported side effects from IV Uptravi were mainly prostacyclin-related or infusion site reactions, and included nausea, vomiting, headache, swelling, and redness. However, none were severe or resulted in treatment discontinuation. All infusion site reactions resolved within four days after the last infusion.
After restarting oral treatment, three serious side effects occurred in two patients with underlying conditions, or comorbidities, such as type 2 diabetes. According to the scientists, those side effects resolved without any further problem, and both patients remained with the oral formulation.
In addition, no changes in WHO functional status were found, and no symptomatic changes in blood pressure were observed among participants.
Exposure to Uptravi’s active metabolite was also similar between corresponding oral and IV doses, indicating similar efficacy.
These results “support the use of IV selexipag [Uptravi] as a temporary option for PAH patients to avoid treatment interruptions during clinical scenarios in which the administration of oral selexipag is not possible,” the team wrote.