PMID- 33536021 OWN - NLM STAT- MEDLINE DCOM- 20211029 LR - 20211029 IS - 1465-993X (Electronic) IS - 1465-9921 (Print) IS - 1465-9921 (Linking) VI - 22 IP - 1 DP - 2021 Feb 3 TI - 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. PG - 34 LID - 10.1186/s12931-020-01594-8 [doi] LID - 34 AB - 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. FAU - Klose, Hans AU - Klose H AD - Department of Respiratory Medicine, Center of Oncology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany. klose@uke.de. FAU - Chin, Kelly M AU - Chin KM AD - Division of Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA. FAU - Ewert, Ralf AU - Ewert R AD - Department of Respiratory Medicine, Clinic of Internal Medicine, Ernst Moritz Arndt University of Greifswald, Greifswald, Germany. FAU - Gall, Henning AU - Gall H AD - University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany. FAU - Parambil, Joseph AU - Parambil J AD - Department of Pulmonary, Allergy and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH, USA. FAU - Poch, David AU - Poch D AD - Department of Pulmonary Critical Care, University of California, San Diego, CA, USA. FAU - Seyfarth, Hans-Jurgen AU - Seyfarth HJ AD - Department of Respiratory Medicine, University of Leipzig, Leipzig, Germany. FAU - Axelsen, Lene N AU - Axelsen LN AD - Actelion Pharmaceuticals Ltd, Allschwil, Switzerland. FAU - Hsu Schmitz, Shu-Fang AU - Hsu Schmitz SF AD - Actelion Pharmaceuticals Ltd, Allschwil, Switzerland. FAU - Stein, Claudia AU - Stein C AD - Actelion Pharmaceuticals Ltd, Allschwil, Switzerland. FAU - Preston, Ioana R AU - Preston IR AD - Pulmonary, Critical Care and Sleep Division, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA. LA - eng SI - ClinicalTrials.gov/NCT03187678 PT - Clinical Trial, Phase III PT - Journal Article PT - Multicenter Study DEP - 20210203 PL - England TA - Respir Res JT - Respiratory research JID - 101090633 RN - 0 (Acetamides) RN - 0 (Antihypertensive Agents) RN - 0 (Pyrazines) RN - 5EXC0E384L (selexipag) SB - IM MH - Acetamides/*administration & dosage/adverse effects/*pharmacokinetics MH - Administration, Intravenous MH - Administration, Oral MH - Aged MH - Antihypertensive Agents/*administration & dosage/adverse effects/*pharmacokinetics MH - Cross-Over Studies MH - Drug Administration Routes MH - Female MH - Headache/chemically induced MH - Humans MH - Male MH - Middle Aged MH - Prospective Studies MH - Pulmonary Arterial Hypertension/diagnosis/*drug therapy/*metabolism MH - Pyrazines/*administration & dosage/adverse effects/*pharmacokinetics PMC - PMC7856757 OTO - NOTNLM OT - Intravenous OT - Pharmacokinetics OT - Pulmonary arterial hypertension OT - Selexipag OT - Treatment interruptions COIS- 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. EDAT- 2021/02/05 06:00 MHDA- 2021/10/30 06:00 PMCR- 2021/02/03 CRDT- 2021/02/04 05:32 PHST- 2020/09/10 00:00 [received] PHST- 2020/12/01 00:00 [accepted] PHST- 2021/02/04 05:32 [entrez] PHST- 2021/02/05 06:00 [pubmed] PHST- 2021/10/30 06:00 [medline] PHST- 2021/02/03 00:00 [pmc-release] AID - 10.1186/s12931-020-01594-8 [pii] AID - 1594 [pii] AID - 10.1186/s12931-020-01594-8 [doi] PST - epublish SO - Respir Res. 2021 Feb 3;22(1):34. doi: 10.1186/s12931-020-01594-8.