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

Abstract

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.

Conflict of interest statement

Funding

This work was supported by Ardelyx. Medical writing support was provided by Richard Claes, PhD, of PharmaGenesis London, London, UK, and was funded by Ardelyx.

Declaration of financial/other relationships

AY, DPR and JWJ are employees of Ardelyx and have ownership interest in Ardelyx.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Figures

Fig. 1

Flow of volunteers through the a SAD–MAD and b dose regimen studies. AE adverse event, b.i.d twice daily, MAD multiple ascending dose, q.d. once daily, SAD single-ascending dose, t.i.d. three times daily. ab.i.d. dose with escalation every other day, daily total 30, 60, or 90 mg. bMaximum 15 g psyllium daily. cReported AEs of abdominal pain and nausea. dIndividual withdrew consent to participate after reporting AEs of abdominal pain and proctalgia

Fig. 2

Daily excretion of sodium via urine in healthy volunteers treated with tenapanor or placebo in the SAD–MAD study a SAD phase and b MAD phase. Data are given as mean ± standard deviation. MAD multiple ascending dose, SAD single ascending dose. aBaseline is the 24-h collection interval ending before dosing on day 1

Fig. 3

Daily excretion of sodium via a stool and b urine in healthy volunteers treated with tenapanor or placebo in the dose regimen study. Data are given as mean ± standard deviation; data for the 15 mg b.i.d., 30 mg b.i.d., 60 mg b.i.d., and placebo cohorts have been reported previously [6]. b.i.d. twice daily, q.d. once daily, t.i.d. three times daily. aBaseline is the mean of values from day − 2 to day − 1. bb.i.d. dose with escalation every other day, daily total 30, 60, or 90 mg. cMaximum 15 g psyllium daily

Fig. 4

a Daily stool frequency, b daily stool weight, and c stool consistency in healthy volunteers treated with tenapanor or placebo in the dose regimen study. Data are given as mean ± standard deviation; stool consistency data for the 15 mg b.i.d., 30 mg b.i.d., 60 mg b.i.d., and placebo cohorts have been reported previously [6]. b.i.d. twice daily, q.d. once daily, t.i.d. three times daily. aBaseline is the 24-h collection interval ending before dosing on day 1 (stool weight: daily average from day − 3 to day − 1). bb.i.d. dose with escalation every other day, daily total 30, 60, or 90 mg. cMaximum 15 g psyllium daily