title: Pharmacokinetics and safety of cavosonstat (N91115) in healthy and cystic fibrosis adults homozygous for F508DEL-CFTR.
abstract: BACKGROUND
  Cavosonstat (N91115), an orally bioavailable inhibitor of S-nitrosoglutathione reductase, promotes cystic fibrosis transmembrane conductance regulator (CFTR) maturation and plasma membrane stability, with a mechanism of action complementary to CFTR correctors and potentiators.
  
  
  METHODS
  A Phase I program evaluated pharmacokinetics, drug-drug interactions and safety of cavosonstat in healthy and cystic fibrosis (CF) subjects homozygous for F508del-CFTR. Exploratory outcomes included changes in sweat chloride in CF subjects.
  
  
  RESULTS
  Cavosonstat was rapidly absorbed and demonstrated linear and predictable pharmacokinetics. Exposure was unaffected by a high-fat meal or rifampin-mediated effects on drug metabolism and transport. Cavosonstat was well tolerated, with no dose-limiting toxicities or significant safety findings. At the highest dose, significant reductions from baseline in sweat chloride were observed (-4.1mmol/L; P=0.032) at day 28.
  
  
  CONCLUSIONS
  The favorable safety and clinical profile warrant further study of cavosonstat in CF. ClinicalTrials.gov Numbers: NCT02275936, NCT02013388, NCT02500667.
authors.affiliation: Cystic Fibrosis Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: scott_donaldson@med.unc.edu.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Donaldson
authors.affiliation: Department of Medicine and the Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, AL, USA.
authors.forename: George M
authors.initials: GM
authors.lastname: Solomon
authors.affiliation: Eudowood Division of Pediatric Respiratory Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Zeitlin
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston, SC, USA; Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Flume
authors.affiliation: Department of Medicine, Division of Respiratory Diseases, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: Casey
authors.affiliation: Ohio State University, Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: McCoy
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO, USA.
authors.forename: Edith T
authors.initials: ET
authors.lastname: Zemanick
authors.affiliation: Nivalis Therapeutics Inc., Boulder, CO, USA.
authors.forename: Arun
authors.initials: A
authors.lastname: Mandagere
authors.affiliation: Nivalis Therapeutics Inc., Boulder, CO, USA.
authors.forename: Janice M
authors.initials: JM
authors.lastname: Troha
authors.affiliation: Nivalis Therapeutics Inc., Boulder, CO, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Shoemaker
authors.affiliation: Department of Pediatrics, Case Western Reserve University School of Medicine and Rainbow Babies and Children's Hospital, Cleveland, OH, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Chmiel
authors.affiliation: Department of Internal Medicine, Pulmonary Division, National Jewish Health, University of Colorado Health Sciences Center, Denver, CO, USA; Department of Pediatrics, Pulmonary Division, National Jewish Health, University of Colorado Health Sciences Center, Denver, CO, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Taylor-Cousar
mesh_terms: D000328:Adult; D000445:Aldehyde Oxidoreductases / Q000037:antagonists & inhibitors*; D000627:Aminophenols / Q000494:pharmacology*; D000631:Aminopyridines / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology*; D001682:Biological Availability; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism; D065701:Cytochrome P-450 CYP3A Inducers / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004347:Drug Interactions; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D049990:Membrane Transport Modulators / Q000494:pharmacology*; D009154:Mutation; D010597:Pharmacogenetics; D015363:Quinolones / Q000494:pharmacology*; D012293:Rifampin / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D000627:Aminophenols; D000631:Aminopyridines; D052117:Benzodioxoles; D001713:Biphenyl Compounds; D065701:Cytochrome P-450 CYP3A Inducers; D004338:Drug Combinations; D049990:Membrane Transport Modulators; D015363:Quinolones; C000626473:cavosonstat; C000599212:lumacaftor, ivacaftor drug combination; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000445:Aldehyde Oxidoreductases; C087006:formaldehyde dehydrogenase, glutathione-independent; D012293:Rifampin
keywords: CFTR stabilizer; Cystic fibrosis; GSNOR, F508del-CFTR; Homozygous; Modulator