title: A FIM study to assess safety and exposure of inhaled single doses of AP301-A specific ENaC channel activator for the treatment of acute lung injury.
abstract: AP301 is an activator of ENaC-mediated Na(+) uptake for the treatment of pulmonary permeability edema in acute respiratory distress syndrome (ARDS). The purpose of this "first-in-man" study was to examine local and systemic safety and systemic exposure of ascending single doses of AP301, when inhaled by healthy male subjects. In a double-blind, placebo-controlled study, 48 healthy male subjects were randomized to 6 ascending dose groups (single doses up to 120 mg) of 8 subjects each (3:1 randomization of AP301: placebo). Serial assessments included spirometry, exhaled nitric oxide (eNO), vital signs, ECG, safety laboratory, adverse events (AE), and blood samples for the quantification of AP301 in plasma. Descriptive statistics was applied. All 48 subjects received treatment, and completed the study as per protocol. No serious, local (e.g., hoarseness, cough, bronchospasm), or dose-limiting AEs were noted. None of the assessments indicated notable dose or time-related alterations of safety outcomes. Observed AP301 systemic exposure levels were very low, with mean Cmax values of <2.5 ng/mL in the highest dose groups. Inhaled AP301 single doses up to 120 mg were safe and well tolerated by healthy male subjects. Distribution of inhaled AP301 was largely confined to the lung, as indicated by very low AP301 systemic exposure levels.
authors: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors: Richard
authors: R
authors: Schwameis
authors: Sandra
authors: S
authors: Eder
authors: Helmut
authors: H
authors: Pietschmann
authors: Bernhard
authors: B
authors: Fischer
authors: Hermann
authors: H
authors: Mascher
authors: Susan
authors: S
authors: Tzotzos
authors: Hendrik
authors: H
authors: Fischer
authors: Rudolf
authors: R
authors: Lucas
authors: Markus
authors: M
authors: Zeitlinger
authors: Robert
authors: R
authors: Hermann
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy; D000280:Administration, Inhalation; D000328:Adult; D001794:Blood Pressure; D004311:Double-Blind Method; D053503:Epithelial Sodium Channels / Q000378:metabolism; D006801:Humans; D008297:Male; D009330:Nebulizers and Vaporizers; D009569:Nitric Oxide / Q000378:metabolism; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D011674:Pulse; D013147:Spirometry; D055815:Young Adult
chemical_list: D053503:Epithelial Sodium Channels; D010456:Peptides, Cyclic; C583752:AP301 peptide; D009569:Nitric Oxide
keywords: AP301; ARDS; ENaC activator; first-in-man study