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J Cyst Fibros. 2017 May;16(3):371-379. doi: 10.1016/j.jcf.2017.01.009. Epub 2017 Feb 13.

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

Author information

1
Cystic Fibrosis Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: scott_donaldson@med.unc.edu.
2
Department of Medicine and the Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, AL, USA.
3
Eudowood Division of Pediatric Respiratory Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
4
Department of Medicine, Medical University of South Carolina, Charleston, SC, USA; Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA.
5
Department of Medicine, Division of Respiratory Diseases, Boston Children's Hospital, Boston, MA, USA.
6
Ohio State University, Nationwide Children's Hospital, Columbus, OH, USA.
7
Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO, USA.
8
Nivalis Therapeutics Inc., Boulder, CO, USA.
9
Department of Pediatrics, Case Western Reserve University School of Medicine and Rainbow Babies and Children's Hospital, Cleveland, OH, USA.
10
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.

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.

KEYWORDS:

CFTR stabilizer; Cystic fibrosis; GSNOR, F508del-CFTR; Homozygous; Modulator

PMID:
28209466
DOI:
10.1016/j.jcf.2017.01.009
[Indexed for MEDLINE]
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