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

Abstract

Background: The oral IP receptor agonist selexipag is approved for the long-term treatment of pulmonary arterial hypertension (PAH). Treatment interruptions should be avoided due to the progressive nature of the disease. An intravenous (IV) formulation of selexipag was developed to provide a treatment option for short-term interruptions to oral selexipag. In this prospective, multicenter, open-label study, the safety, tolerability, and pharmacokinetics of temporarily switching between oral and IV selexipag were investigated (NCT03187678, ClinicalTrials.gov).

Methods: PAH patients receiving stable oral selexipag doses were enrolled. Following three consecutive IV selexipag infusions patients resumed oral selexipag. Corresponding IV and oral doses were selected to achieve comparable exposure to the active metabolite of selexipag. Safety outcomes were monitored throughout, and pharmacokinetic samples were obtained after oral and IV administration.

Results: All 20 patients completed the study. Fifteen patients had adverse events (AEs), most were mild, and none resulted in discontinuation. Headache was the most common AE throughout the study (four patients). Three serious AEs occurred in two patients with underlying comorbidities when oral dosing had resumed. There were no changes in WHO functional class for any patient and no clinically symptomatic changes in blood pressure were observed. Comparable exposure to the active metabolite of selexipag was demonstrated following corresponding oral and IV selexipag doses.

Conclusions: Temporarily switching between corresponding doses of oral and IV selexipag was well-tolerated with no unexpected safety findings and comparable exposure to the active metabolite. Treatment with IV selexipag is a feasible option to bridge temporary oral selexipag treatment interruptions.

Keywords: Intravenous; Pharmacokinetics; Pulmonary arterial hypertension; Selexipag; Treatment interruptions.

Conflict of interest statement

HK has received honoraria and/or other support from Bayer, Janssen Pharmaceutical Companies of Johnson & Johnson, MSD, OMT and United Therapeutics. KC has received honoraria and/or fees for consultancy and steering/adjudication committees from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer (through the University of California, San Diego), United Therapeutics and Gossamer Bio. KC’s institution has received grants, research support from Janssen Pharmaceutical Companies of Johnson & Johnson, Ironwood Pharmaceuticals, the National Institute of Health and SoniVie, and she has received financial/material support from the American Heart Association. RE has received honoraria and/or fees for consultancy from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer Vital and OMT and as a corporate board member for Actelion Pharmaceuticals Ltd, OMT and Novartis. RE has received grants from Janssen Pharmaceutical Companies of Johnson & Johnson, Boehringer Ingelheim, OMT, Berlin Chemie and Novartis. HG has received fees and/or honoraria and/or other support from Janssen Pharmaceutical Companies of Johnson & Johnson, AstraZeneca, Bayer, Bristol–Myers Squibb, GlaxoSmithKline, Lilly, MSD, Novartis, OMT, Pfizer and United Therapeutics. JP has nothing to declare. DP has received consultant/speaker’s bureau honoraria and/or fees from Bayer. HJS has received advisory board honoraria and/or fees and/or grants and research support from Janssen Pharmaceutical Companies of Johnson & Johnson and has received financial support and/or speaker honoraria from Bayer and GlaxoSmithKline. LNA, SHS and CS are employees of Actelion Pharmaceuticals Ltd, a Janssen Pharmaceutical Company of Johnson & Johnson; SHS is a stock holder in Novartis, Alcon, and stock option holder in Janssen Pharmaceutical Companies of Johnson & Johnson, LNA is a stock holder in Novo Nordisk A/S and Zealand Pharma A/S and CS is stock holder in Novartis, Organovo, Idorsia Pharmaceuticals Ltd., and stock option holder in Janssen Pharmaceutical Companies of Johnson & Johnson. IRP has received consultant and scientific medical advisor honoraria and/or fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Arena, Gilead, United Therapeutics, Liquidia, Pfizer and Acceleron. IRP’s institution has received grants and research support from Janssen Pharmaceutical Companies of Johnson & Johnson, Acceleron, Arena, Gilead, United Therapeutics, Liquidia and Bayer.

Figures

Fig. 1

Study design. IV, intravenous; PAH, pulmonary arterial hypertension

Fig. 2

Mean (bold red line) and individual changes in systolic and diastolic blood pressure from pre-dose values during IV infusion 1 (Day 2) and IV infusion 3 (Day 3). IV, intravenous

Fig. 3

Pharmacokinetic profiles of a selexipag and b the active metabolite (ACT-333679) following oral and IV selexipag. N = 20, values are dose-normalized concentrations. AUCΤ, ss, area under the plasma concentration–time curve during a dose interval at steady state; Cmax, ss, maximum plasma concentration at steady state; IV, intravenous; SD, standard deviation