title: Acute hyperkalemia associated with inhalation of a potent ENaC antagonist: Phase 1 trial of GS-9411.
abstract: BACKGROUND
  Inhaled epithelial sodium channel (ENaC) blockers are designed to increase airway surface liquid volume, thereby benefiting cystic fibrosis patients. This study evaluated the safety, tolerability, and pharmacokinetics of multiple doses of ENaC blocker GS-9411, in healthy participants.
  
  
  METHODS
  This randomized, double-blind, placebo-controlled, parallel-group, residential, Phase 1 study evaluated inhaled GS-9411 (2.4, 4.8, and 9.6 mg) or placebo, dosed twice daily for 14 days.
  
  
  CONCLUSIONS
  GS-9411 was well tolerated; 86.1% of treated participants completed dosing (n=31/36). Cough and dizziness (27.8% participants each; most of mild severity) were the most commonly reported adverse events and occurred in both placebo and GS-9411 treatment groups. Arrhythmias were not observed for GS-9411-treated participants, and electrocardiographic changes were not considered clinically significant. Serum potassium levels exceeded the upper limit of normal (>5 mmol/L), 4 hr after the morning dose in GS-9411 (n=16/24) and placebo (n=4/12) treatment groups (38 incidences total). Retesting revealed levels had returned to normal within 2-3 hr. In urine electrolyte analyses, obtained 0-6 hr after the Day 1 morning dose, mean sodium/potassium ratios significantly increased from values 0-6 hr before dosing. Increased urine sodium/potassium ratios corresponded with high urine concentrations of active GS-9411 metabolites, which inhibited sodium reabsorption in the kidney, leading to the observed transient hyperkalemia in these participants. Inhaled GS-9411 was well tolerated except for the emergence of transient clinically significant hyperkalemia; this finding resulted in termination of further clinical development of this drug and will necessitate development of a new generation of ENaC blockers, which provide a sustained improvement in mucociliary clearance, while reducing renal exposure to ENaC blockade. Transient increases in mean urine sodium/potassium ratios appeared to be the first signal of electrolyte imbalances resulting from drug-induced block of ENaC in the kidney. The results of this study strongly suggest that clinical trials of novel ENaC blockers will require intensive measurement of plasma and urine electrolyte levels.
authors.affiliation: 1 Gilead Sciences Inc. , Seattle, WA 98102.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: O'Riordan
authors.forename: Karl H
authors.initials: KH
authors.lastname: Donn
authors.forename: Peter
authors.initials: P
authors.lastname: Hodsman
authors.forename: John H
authors.initials: JH
authors.lastname: Ansede
authors.forename: Terry
authors.initials: T
authors.lastname: Newcomb
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Lewis
authors.forename: William D
authors.initials: WD
authors.lastname: Flitter
authors.forename: Vicki Shigekane
authors.initials: VS
authors.lastname: White
authors.forename: M Ross
authors.initials: MR
authors.lastname: Johnson
authors.forename: A Bruce
authors.initials: AB
authors.lastname: Montgomery
authors.forename: David G
authors.initials: DG
authors.lastname: Warnock
authors.forename: Richard C
authors.initials: RC
authors.lastname: Boucher
mesh_terms: D000208:Acute Disease; D000280:Administration, Inhalation; D000328:Adult; D001315:Australia; D015415:Biomarkers / Q000097:blood / Q000652:urine; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D062686:Epithelial Sodium Channel Blockers / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D006947:Hyperkalemia / Q000097:blood / Q000139:chemically induced* / Q000175:diagnosis / Q000652:urine; D008297:Male; D011188:Potassium / Q000097:blood* / Q000652:urine; D018570:Risk Assessment; D055815:Young Adult
chemical_list: D015415:Biomarkers; D062686:Epithelial Sodium Channel Blockers; D011188:Potassium
keywords: amiloride; cystic fibrosis; epithelial sodium channels; potassium-sparing diuretic; renal potassium excretion; urine electrolytes