Tenapanor administration and the activity of the H + -coupled transporter PepT1 in healthy volunteers.

Aim: Tenapanor (RDX5791/AZD1722), an inhibitor of gastrointestinal Na ⁺ /H ⁺ exchanger NHE3, is being evaluated for the treatment of patients with constipation-predominant irritable bowel syndrome and the treatment of hyperphosphataemia in patients with chronic kidney disease on dialysis. By reducing intestinal H ⁺ secretion, inhibition of NHE3 by tenapanor could indirectly affect H ⁺ -coupled transporter activity, leading to drug-drug interactions. We investigated the effect of tenapanor on the activity of the H ⁺ -coupled peptide transporter PepT1 via assessment of the pharmacokinetics of cefadroxil - a compound transported by PepT1 - in healthy volunteers.
Methods: In this open-label, two-period crossover, phase 1 study (NCT02140281), 28 volunteers received in random order: a single dose of cefadroxil 500 mg for 1 day; and tenapanor 15 mg twice daily over 4 days followed by single doses of both cefadroxil 500 mg and tenapanor 15 mg on day 5. There was a 4-day washout between treatment periods.
Results: Cefadroxil exposure was similar when administered alone or in combination with tenapanor {geometric least-squares mean ratios [(cefadroxil + tenapanor)/cefadroxil] (90% confidence interval): area under the concentration-time curve 93.3 (90.6-96.0)%; maximum concentration in plasma 95.9 (89.8-103)%}. Tenapanor treatment caused a softening of stool consistency and an increase in stool frequency, consistent with its expected pharmacodynamic effect. No safety concerns were identified and tenapanor was not detected in plasma.
Conclusions: These results suggest that tenapanor 15 mg twice daily does not have a clinically relevant impact on the activity of the H ⁺ -coupled transporter PepT1 in humans. This may guide future research on drug-drug interactions involving NHE3 inhibitors.
(© 2017 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)