Pharmacodynamics, Safety, and Tolerability of the NHE3 Inhibitor Tenapanor: Two Trials in Healthy Volunteers

Clin Drug Investig. 2018 Apr;38(4):341-351. doi: 10.1007/s40261-017-0614-0.


Background: Tenapanor, a small molecule with minimal systemic availability, is a first-in-class sodium/hydrogen exchanger 3 (NHE3) inhibitor that acts in the gut. Here, we evaluate the pharmacodynamics and safety of tenapanor in healthy adults.

Methods: Two phase I, single-center, randomized, double-blind, placebo-controlled studies were performed. The first study assessed single-ascending oral tenapanor doses of 10, 50, 150, 450, and 900 mg (n = 8 per group; six tenapanor, two placebo) and multiple ascending doses over 7 days of 3, 10, 30, and 100 mg q.d. (n = 10 per group; eight tenapanor, two placebo). In the second study, different tenapanor regimens were evaluated over 7 days (n = 15 per group; 12 tenapanor, three placebo): 15 mg twice daily (b.i.d.), 30 mg once daily (q.d.), 30 mg b.i.d., 30 mg three times daily (t.i.d.), 60 mg b.i.d., escalating b.i.d. dose (daily total 30-90 mg), 30 mg b.i.d. with psyllium.

Results: Tenapanor produced generally dose-dependent increases in stool sodium excretion and decreases in urinary sodium excretion versus placebo; in addition, twice-daily dosing appeared to have a greater effect on sodium absorption than once-daily dosing with an equivalent daily dose. Tenapanor softened stool consistency and increased stool frequency and weight from baseline versus placebo. Tenapanor concentrations were below the quantification limit (0.5 ng/ml) in 98.5% of 895 plasma samples. Adverse events were mild or moderate in severity, and were typically gastrointestinal in nature. There were no clinically relevant changes in serum electrolytes.

Conclusions: Tenapanor was well tolerated and resulted in reduced intestinal sodium absorption and softer stool consistency versus placebo. Systemic exposure to tenapanor was minimal. These results support potential use of tenapanor in patients who could benefit from modification of gastrointestinal sodium balance. CLINICALTRIALS.

Gov identifiers: NCT02819687, NCT02796131.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aged
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Administration Schedule
  • Feces / chemistry
  • Female
  • Healthy Volunteers
  • Humans
  • Isoquinolines / adverse effects*
  • Isoquinolines / blood
  • Isoquinolines / pharmacokinetics
  • Isoquinolines / pharmacology*
  • Laxatives / adverse effects
  • Laxatives / pharmacokinetics
  • Laxatives / pharmacology
  • Male
  • Middle Aged
  • Sodium / analysis
  • Sodium / urine
  • Sulfonamides / adverse effects*
  • Sulfonamides / blood
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / pharmacology*
  • Young Adult


  • Isoquinolines
  • Laxatives
  • Sulfonamides
  • Sodium
  • tenapanor

Associated data