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Original Research: Genetic and Developmental Disorders |

Reduced Sodium Transport With Nasal Administration of the Prostasin Inhibitor Camostat in Subjects With Cystic FibrosisReduced Sodium Transport With Prostasin Inhibition

Steven M. Rowe, MD, MSPH; Ginger Reeves, CCRC; Heather Hathorne, CCRC; G. Martin Solomon, MD; Smita Abbi, PhD; Didier Renard, PhD; Ruth Lock, PhD; Ping Zhou, PhD; Henry Danahay, PhD; John P. Clancy, MD; David A. Waltz, MD
Author and Funding Information

From the Department of Medicine (Dr Rowe), Department of Pediatrics (Dr Rowe and Mss Reeves and Hathorne), Department of Physiology and Biophysics (Dr Rowe), and Cystic Fibrosis Research Center (Drs Rowe and Solomon and Mss Reeves and Hathorne), University of Alabama at Birmingham, Birmingham, AL; Novartis Institutes for BioMedical Research (Dr Abbi), East Hanover, NJ; Novartis Institutes for BioMedical Research (Dr Renard), Basel, Switzerland; Novartis Institutes for BioMedical Research (Drs Lock, Zhou, and Danahay), Horsham, England; Department of Pediatrics (Dr Clancy), Cincinnati Children’s Hospital Medical Center, and University of Cincinnati, Cincinnati, OH; and Novartis Institutes for BioMedical Research (Dr Waltz), Cambridge, MA.

Correspondence to: Steven M. Rowe, MD, MSPH, University of Alabama at Birmingham, MCLM 768, 1918 University Blvd, Birmingham, AL 35294-0006; e-mail: smrowe@uab.edu


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

Funding/Support: This research was funded by Novartis Pharma US and supported by the National Institutes of Health [K23 DK075788 to Dr Rowe, P30 DK072482, and 5UL1 RR025777] and the Cystic Fibrosis Foundation [CLANCY09Y0 and CLANCY05Y2 to Dr Rowe].


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

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