title: Preclinical and Healthy Volunteer Studies of Potential Drug-Drug Interactions Between Tenapanor and Phosphate Binders.
abstract: Tenapanor (RDX5791, AZD1722), a first-in-class small molecule with minimal systemic availability, is an inhibitor of the sodium/hydrogen exchanger isoform 3. Tenapanor acts locally in the gut, where it reduces absorption of sodium and phosphate. It is being studied in patients with chronic kidney disease requiring dialysis, who are often administered phosphate binders such as sevelamer to help control hyperphosphatemia. We investigated whether coadministration of tenapanor with phosphate binders (sevelamer or calcium-based binders) impacts the pharmacodynamic effects of tenapanor. In vitro studies suggested a binding interaction between tenapanor and sevelamer, but this did not translate into altered pharmacodynamic effects in rats. An open-label, 2-way crossover study was then conducted in healthy volunteers (NCT02346890). This showed that 4 days' treatment with tenapanor hydrochloride (15 mg twice daily) with or without sevelamer carbonate (800 mg 3 times daily) resulted in comparable 24-hour stool and urinary sodium and phosphorus levels. Stool frequency, consistency, and weight were also comparable between the treatments. These results suggest that the binding between sevelamer and tenapanor observed in vitro does not translate into altered pharmacodynamic effects in humans.
authors.affiliation: AstraZeneca Gothenburg, Mölndal, Sweden.
authors.forename: Susanne
authors.initials: S
authors.lastname: Johansson
authors.affiliation: AstraZeneca Gothenburg, Mölndal, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Leonsson-Zachrisson
authors.affiliation: AstraZeneca Gothenburg, Mölndal, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Knutsson
authors.affiliation: Formerly of Ardelyx Inc., Fremont, CA, USA.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Spencer
authors.affiliation: Formerly of Ardelyx Inc., Fremont, CA, USA.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Labonté
authors.affiliation: Formerly of Ardelyx Inc., Fremont, CA, USA.
authors.forename: Desiree
authors.initials: D
authors.lastname: Deshpande
authors.affiliation: Ardelyx Inc., Fremont, CA, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Kohler
authors.affiliation: Ardelyx Inc., Fremont, CA, USA.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kozuka
authors.affiliation: Formerly of Ardelyx Inc., Fremont, CA, USA.
authors.forename: Dominique
authors.initials: D
authors.lastname: Charmot
authors.affiliation: Ardelyx Inc., Fremont, CA, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Rosenbaum
mesh_terms: D000328:Adult; D000818:Animals; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010758:Phosphorus / Q000652:urine*; D011897:Random Allocation; D051381:Rats; D000069603:Sevelamer / Q000008:administration & dosage* / Q000494:pharmacology; D012964:Sodium / Q000652:urine*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D007546:Isoquinolines; D013449:Sulfonamides; D010758:Phosphorus; D012964:Sodium; D000069603:Sevelamer; C000599417:tenapanor
keywords: chronic kidney disease; drug-drug interactions; hyperphosphatemia; sodium absorption; tenapanor