A phase 1 study of the safety, tolerability, pharmacodynamics, and pharmacokinetics of tenapanor in healthy Japanese volunteers

Susanne Johansson, David P Rosenbaum, Mikael Knutsson, Maria Leonsson-Zachrisson, Susanne Johansson, David P Rosenbaum, Mikael Knutsson, Maria Leonsson-Zachrisson

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Chronic kidney disease; NHE3 protein; Phosphate absorption; Sodium absorption; Sodium, dietary; Tenapanor.

Conflict of interest statement

Conflict of interest

SJ is an employee of and has ownership interests in AstraZeneca. DR is an employee of and has ownership interests in Ardelyx. MK and ML-Z are employees of AstraZeneca.

Funding

This study was funded by AstraZeneca.

Figures

Fig. 1
Fig. 1
Excretion of sodium via a stool and b urine in healthy Japanese volunteers treated with tenapanor or placebo. Data are shown as mean + SD; corresponding values given above the bars show mean (SD).  a daily mean over 7 days.  b combined data from participants receiving single (n = 2) and repeated (n = 12) doses (one individual in the placebo group was excluded from stool analyses owing to a lack of any post-baseline samples). SD standard deviation
Fig. 2
Fig. 2
Excretion of phosphorus via a stool and b urine in Japanese healthy volunteers treated with tenapanor or placebo. Data are shown as mean + SD; corresponding values given above the bars show mean (SD).  a daily mean over 7 days.  b combined data from participants receiving single (n = 2) and repeated (n = 12) doses (one individual in the placebo group was excluded from stool analyses owing to a lack of any post-baseline samples). SD standard deviation

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