Reduced sodium transport with nasal administration of the prostasin inhibitor camostat in subjects with cystic fibrosis

Chest. 2013 Jul;144(1):200-207. doi: 10.1378/chest.12-2431.

Abstract

Background: Prostasin, a trypsin-like serine protease, is a channel-activating protease and major regulator of epithelial sodium channel-mediated sodium absorption. Its direct inhibition by camostat represents a potential approach to inhibiting sodium transport in cystic fibrosis (CF).

Methods: To determine whether a topical formulation of camostat represents an efficacious and tolerable approach to reducing Na+ transport in the CF airway, we conducted a two-part randomized, double-blind, placebo-controlled, crossover, ascending single-dose study to evaluate the pharmacodynamics, safety, and pharmacokinetics of camostat administered through a nasal spray pump in subjects with CF. Nasal potential difference (PD) was measured before and after treatment, and safety and pharmacokinetics were assessed by a standardized approach.

Results: In part 1, nine subjects were enrolled, and six completed crossover dosing at the maximally tolerated dose. The change in maximal (most polarizing) basal PD 2 h following administration of camostat was +13.1 mV (1.6-mg dose group) compared with -8.6 mV following placebo (P<.005). Intrasubject change in Ringer and amiloride-sensitive PDs exhibited similar and consistent responses. Bayesian analysis in an additional six subjects in part 2 estimated a dose of 18 μg/mL to provide 50% of the maximum effect. There was no significant change in chloride transport or total nasal symptom score, nasal examination rating, and laboratory parameters.

Conclusions: This study establishes the proof of concept that a reduction in sodium transport in the human CF airway can be achieved through inhibition of prostasin activity, identifying a potential therapeutic target in the disease.

Trial registration: ClinicalTrials.gov; No.: NCT00506792; URL: www.clinicaltrials.gov.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intranasal
  • Adult
  • Biological Transport / drug effects
  • Chlorides / metabolism
  • Cross-Over Studies
  • Cystic Fibrosis / metabolism*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Tolerance
  • Female
  • Gabexate / administration & dosage
  • Gabexate / analogs & derivatives*
  • Gabexate / pharmacokinetics
  • Gabexate / pharmacology
  • Humans
  • Male
  • Middle Aged
  • Protease Inhibitors / administration & dosage
  • Protease Inhibitors / pharmacokinetics
  • Protease Inhibitors / pharmacology*
  • Respiratory System / metabolism*
  • Serine Endopeptidases / drug effects*
  • Sodium / metabolism*
  • Treatment Outcome

Substances

  • Chlorides
  • Protease Inhibitors
  • camostat
  • Gabexate
  • Sodium
  • Serine Endopeptidases
  • prostasin

Associated data

  • ClinicalTrials.gov/NCT00506792