Pharmacokinetics and safety of cavosonstat (N91115) in healthy and cystic fibrosis adults homozygous for F508DEL-CFTR.

Academic Article

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.
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    Keywords

  • CFTR stabilizer, Cystic fibrosis, GSNOR, F508del-CFTR, Homozygous, Modulator, Adult, Aldehyde Oxidoreductases, Aminophenols, Aminopyridines, Benzodioxoles, Biological Availability, Biphenyl Compounds, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Cytochrome P-450 CYP3A Inducers, Dose-Response Relationship, Drug, Drug Combinations, Drug Interactions, Drug Monitoring, Female, Humans, Male, Membrane Transport Modulators, Mutation, Pharmacogenetics, Quinolones, Rifampin, Treatment Outcome
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    Author List

  • Donaldson SH; Solomon GM; Zeitlin PL; Flume PA; Casey A; McCoy K; Zemanick ET; Mandagere A; Troha JM; Shoemaker SA
  • Start Page

  • 371
  • End Page

  • 379
  • Volume

  • 16
  • Issue

  • 3