title: A phase 1 study of the safety, tolerability, pharmacodynamics, and pharmacokinetics of tenapanor in healthy Japanese volunteers.
abstract: Tenapanor (RDX5791, AZD1722), a small molecule with minimal systemic availability, is an inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3). Tenapanor acts locally in the gut to reduce absorption of sodium and phosphate. It is being developed for the treatment of patients with hyperphosphatemia in CKD requiring dialysis and patients with constipation-predominant irritable bowel syndrome. We report the safety, pharmacodynamics, and pharmacokinetics of tenapanor in Japanese volunteers.
  
  
  
  In this phase 1, double-blind study (NCT02176252), healthy Japanese adults (aged 20-45 years) received single-dose tenapanor 180 mg (n = 6), repeated-dose tenapanor 15, 30, 60, or 90 mg twice daily (n = 12 each) for 7 days, or placebo (n = 14). All participants received a standardized diet.
  
  
  
  Single and repeated doses of tenapanor resulted in higher mean stool sodium content vs. placebo (single dose, 41.9 mmol/day; repeated dose, range of means 21.3-32.2 mmol/day; placebo, 4.1 mmol/day) accompanied by lower urinary sodium content (single dose, 110 mmol/day; repeated dose, 101-112 mmol/day; placebo, 143 mmol/day). Additionally, stool phosphorus content was increased (single dose, 31.0 mmol/day; repeated dose, 17.6-24.8 mmol/day; placebo, 16.8 mmol/day) and urinary phosphorus content decreased (single dose, 18.7 mmol/day; repeated dose, 15.3-19.4 mmol/day; placebo, 25.5 mmol/day). Tenapanor had minimal systemic exposure, provided a softer stool consistency, and was well tolerated.
  
  
  
  Tenapanor treatment reduced absorption of intestinal sodium and phosphate from the gut in Japanese adults. Tenapanor had minimal systemic exposure and was well tolerated. Further research into the clinical benefits of tenapanor is warranted.
authors.affiliation: AstraZeneca Gothenburg, Mölndal, Sweden.
authors.forename: Susanne
authors.initials: S
authors.lastname: Johansson
authors.affiliation: Ardelyx, Inc., 34175 Ardenwood Blvd, Fremont, CA, 94555, USA. drosenbaum@ardelyx.com.
authors.forename: David P
authors.initials: DP
authors.lastname: Rosenbaum
authors.affiliation: AstraZeneca Gothenburg, Mölndal, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Knutsson
authors.affiliation: AstraZeneca Gothenburg, Mölndal, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Leonsson-Zachrisson
mesh_terms: D000328:Adult; D044466:Asian People; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005243:Feces / Q000737:chemistry; D005260:Female; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D064368:Healthy Volunteers; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D007546:Isoquinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D007564:Japan; D008297:Male; D008875:Middle Aged; D010758:Phosphorus / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D000074083:Sodium-Hydrogen Exchanger 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D005765:Gastrointestinal Agents; D007546:Isoquinolines; C000613385:SLC9A3 protein, human; D000074083:Sodium-Hydrogen Exchanger 3; D013449:Sulfonamides; D010758:Phosphorus; D012964:Sodium; C000599417:tenapanor
keywords: Chronic kidney disease; NHE3 protein; Phosphate absorption; Sodium absorption; Sodium, dietary; Tenapanor