rifampin and lumacaftor--ivacaftor-drug-combination

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.. 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.. 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.. The favorable safety and clinical profile warrant further study of cavosonstat in CF. ClinicalTrials.gov Numbers: NCT02275936, NCT02013388, NCT02500667.

Topics: 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