A pharmacokinetic evaluation of tenapanor for the treatment of irritable bowel syndrome with constipation: an update of the literature

ABSTRACT

Introduction

Tenapanor is the latest addition to the second-line pharmacotherapeutic options for the treatment of irritable bowel syndrome with constipation. It is a first-in-class inhibitor of type 3 sodium/hydrogen exchanger (NHE3), characterized by very low oral absorption. Its pharmacological properties are discussed here based on the latest literature.

Areas covered

A general description of tenapanor is provided, highlighting those pharmacokinetic and pharmacodynamic characteristics of the drug which may be of major importance for tolerability and safety. This description is associated with a summary and analysis of currently available toxicological data.

Expert opinion

Plasma concentrations of free tenapanor after oral administration are well below the half maximal inhibitory concentration for NHE3, so that systemic effects of the drug are minimal. Therefore, the action of tenapanor is limited to NHE3 located on the apical membrane of enterocytes. The consequent reduction in intestinal sodium absorption increases the intraluminal content by osmosis, which in turn enhances the propulsive activity of the colon. Diarrhea is the most frequent adverse effect of tenapanor. Increased fecal sodium and water excretion do not appear to expose patients to short- and long-term hydro-electrolyte imbalances.

KEYWORDS:

• Tenapanor
• type 3 sodium/hydrogen exchanger
• NHE3
• irritable bowel syndrome
• IBS

Article highlights

• Tenapanor belongs to a category of second-line treatments for irritable bowel syndrome with constipation (IBS-C), including prosecretory drugs, which act topically on molecular targets located on the luminal membrane of the gastrointestinal epithelium.

• It is the first sodium/hydrogen exchanger type 3 (NHE3) inhibitor approved for clinical use. By reducing the gastrointestinal absorption of sodium, tenapanor induces retention of sodium in the intestinal lumen and thus water by osmosis.

• The increase in intestinal content induced by tenapanor enhances the propulsive contractile activity of the intestine. In healthy volunteers, tenapanor rapidly increases stool frequency and weight by approximately two to three times and reduces stool consistency.

• The gastrointestinal absorption of tenapanor is very low and the plasma free drug levels observed after oral administration are well below the half maximal inhibitory concentration for NHE3. Its action is therefore localized almost exclusively in the gastrointestinal lumen.

• The therapeutic gain with tenapanor compared to placebo in IBS-C, as assessed by the ‘6/12 week’ combined responder rate, is approximately 10.5% at 12 weeks and is maintained at 26 weeks. The most common adverse event with tenapanor is diarrhea with an incidence of 11.1% at 52 weeks. The approximately 20-fold increase in fecal sodium excretion does not appear to cause hydro-electrolyte imbalances at 52 weeks.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosure

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.