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

Academic Article

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.
  • Published In

  • Chest  Journal
  • Keywords

  • Administration, Intranasal, Adult, Biological Transport, Chlorides, Cross-Over Studies, Cystic Fibrosis, Dose-Response Relationship, Drug, Double-Blind Method, Drug Tolerance, Female, Gabexate, Humans, Male, Middle Aged, Protease Inhibitors, Respiratory System, Serine Endopeptidases, Sodium, Treatment Outcome
  • Digital Object Identifier (doi)

    Authorlist

  • Rowe SM; Reeves G; Hathorne H; Solomon GM; Abbi S; Renard D; Lock R; Zhou P; Danahay H; Clancy JP
  • Start Page

  • 200
  • End Page

  • 207
  • Volume

  • 144
  • Issue

  • 1