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

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.

Figures

Figure 1.

Study design, with randomization schemes for part 1 and part 2. A, Part 1 included two panels of subjects (three subjects per group) with repeat dosing and crossover design. B, Part 2 doses were determined using a Bayesian dose-response analysis and administered in the crossover design. A:P = active:placebo dosing ratio; MTD = maximally tolerated dose up to 1.6 mg.

Figure 2.

Flow of subjects through the study.

Figure 3.

Effect of camostat on maximal basal PD. A, B, Representative basal PD tracing of subjects treated with camostat 1.6 mg (A) and placebo (B). Predose and 2-h postdose tracings are shown for the same nostril and the same subject on the left and right sides of A and B, respectively. Maximal basal PD is designated with the gray bar. C, D, Maximal basal PD for each individual subject (●) and the mean of all subjects (○) treated with camostat 1.6 mg (C) and placebo (D). ***P < .005. Data are presented as mean ± SEM. AT = anterior tip of the inferior turbinate; PD = potential difference.

Figure 4.

Effect of camostat on nasal PD perfusion tracings. Tracings were obtained in the target nostril about 2 h following intranasal administration of camostat or placebo. A, Representative nasal PD tracings for a subject treated with camostat 1.6 mg and placebo. The nostril was sequentially perfused with Ringer, amiloride (100 μmol/L), Cl-free gluconate, Cl-free gluconate plus isoproterenol 100 μmol/L, and ATP 10 μmol/L. B, Summary data indicating the mean PD of that shown in A for subjects treated with camostat 1.6 mg and placebo. The Ringer PD and change in PD following amiloride perfusion each reflect sodium transport, whereas the change with Cl-free (zero Cl−), Cl-free isoproterenol and ATP reflect anion conductance. *P = .05; aP = .09. Data are mean ± SEM. ATP = adenosine triphosphate. See Figure 3 legend for expansion of other abbreviation.

Figure 5.

Effect of various doses of camostat on the maximal basal PD. Maximal basal PD was measured predose and 2 h postdose. A, B, and C, Part 1 included camostat 0.200, 0.800, and 1.600 mg and placebo. D, E, and F, Part 2 included camostat 0.005, 0.010, and 0.020 mg and placebo. The Ringers PD by dose (B and E) and change in PD following amiloride perfusion by dose (C and F) for each part of the study are shown. *P < .05; **P < .005; ***P < .001; aP = .09; mean ± SEM. See Figure 3 legend for expansion of abbreviation.

Figure 6.

Dose-response relationship for camostat. The change in maximal basal PD is plotted for each individual subject for parts 1 and 2. The dose-response curve was obtained as a result of the Bayesian analysis. Placebo values were assigned a small (0.1 μg) value for graphical presentation in this figure (log scale). See Figure 3 legend for expansion of abbreviation.