title: Phase I safety study of ranolazine in pulmonary arterial hypertension.
abstract: Pulmonary arterial hypertension (PAH) causes right ventricular ischemia, dysfunction, and failure. PAH patients may benefit from antianginal agents based on a shared pathophysiology with left ventricular ischemia. A single-center, randomized, placebo-controlled trial (1∶1) to assess the acute vasoreactivity and safety of ranolazine in PAH was conducted. Plasma samples for pharmacokinetic (PK) studies were drawn during hemodynamic measurements at 0, 60, 90, 120, 240, and 360 minutes from a Swan-Ganz catheter. All patients received 500-mg doses, uptitrated to 1,000 mg at week 4, monthly evaluations, and a complete objective assessment after 12 weeks, followed by an open-label extension. Thirteen patients were randomized and 12 enrolled (6 ranolazine, 6 placebo). All patients completed the acute phase; 10 completed the 12-week study. There were no acute changes in invasive hemodynamics. At 12 weeks ranolazine was well tolerated. Only 1 of the 5 patients on ranolazine had a serum concentration considered to be in the therapeutic range. Two serious adverse events required early withdrawal (both in the ranolazine group); gastrointestinal complaints were the most common adverse event. Efficacy measures did not demonstrate any differences between treatment groups. During the open-label trial, 2 additional patients reached a therapeutic concentration. Ranolazine in PAH appears safe, without acute hemodynamic effects after a 500-mg dose. Ranolazine administrated to PAH patients receiving background PAH therapies did not consistently reach therapeutic levels. Future studies should first perform PK analysis in PAH patients receiving PAH therapies and explore the safety and tolerability of the higher doses perhaps necessary to achieve therapeutic levels in PAH patients. (
  
  
  BACKGROUND
  Clinicaltrials.gov identifier NCT01757808.).
authors.affiliation: Section of Cardiology, Department of Medicine, University of Chicago, Chicago, Illinois, USA ; Committee on Clinical Pharmacology and Pharmacogenomics, Department of Medicine, University of Chicago, Chicago, Illinois, USA.
authors.forename: Mardi
authors.initials: M
authors.lastname: Gomberg-Maitland
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, School of Medicine, Case Western University, Cleveland, Ohio, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Schilz
authors.affiliation: Section of Cardiology, Department of Medicine, University of Chicago, Chicago, Illinois, USA.
authors.forename: Anuj
authors.initials: A
authors.lastname: Mediratta
authors.affiliation: Section of Cardiology, Department of Medicine, University of Chicago, Chicago, Illinois, USA.
authors.forename: Karima
authors.initials: K
authors.lastname: Addetia
authors.affiliation: Section of Cardiology, Department of Medicine, University of Chicago, Chicago, Illinois, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Coslet
authors.affiliation: Section of Cardiology, Department of Medicine, University of Chicago, Chicago, Illinois, USA ; Committee on Clinical Pharmacology and Pharmacogenomics, Department of Medicine, University of Chicago, Chicago, Illinois, USA.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Thomeas
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Hunter
authors.initials: H
authors.lastname: Gillies
authors.affiliation: Division of Cardiology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Oudiz
keywords: pulmonary arterial hypertension; right ventricular failure