Tenapanor: new approach to counter irritable bowel syndrome with constipation
DOI:
https://doi.org/10.18203/2319-2003.ijbcp20202961Keywords:
Tenapanor, Inflammatory bowel syndrome, NHE3 antagonist, ConstipationAbstract
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder chronic in nature and characterized predominantly by abdominal pain or discomfort associated with altered bowel habits, diagnosis requires characteristic symptoms during the last 3 months and onset ≥6 months ago. Symptom-based approaches for functional bloating, constipation and diarrhea are best utilised to identify IBS. IBS with constipation exerts significant impairment on work productivity by hampering quality of life. Inadequate relief by existing modalities, persistent hard stools and visceral abdominal pain demanded further clinical research. Tenanapor a novel molecule acts locally on gastrointestinal sodium/hydrogen exchanger isoform 3 (NHE3), an antiporter a counter transporter and exert antinociceptive effects on visceral sensation thereby decreases the frequency of abdominal pain. Action on NHE3 receptors located on small intestine and colon’s apical surface reduces the absorption of sodium and phosphate, with minimal systemic exposure. NHE3 Inhibition induced sodium absorption results in increase in water secretion into intestinal lumen resultant an accelerated intestinal transit time and softer stool consistency. Most common adverse reactions (≥2%) are diarrhea, abdominal distension, flatulence and dizziness. The drug is metabolised mainly by CYP3A4/5 and excreted in feaces (70%) and urine (7%). Tenapanor’s minimal systemic absorption is likely to be associated with a relatively inert safety and tolerability profile. Based on positive results from the phase III T3MPO trial program, tenapanor demonstrated promising results for IBS-C management and received US Food and Drug Administration approval as IBSRELA @ Ardelyx Pharma in September 2019 and augment existing modalities for management of IBS-C.
References
Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology. 2006;130:1480-91.
Canavan C, West J, Card T. The epidemiology of irritable bowel syndrome. Clin Epidemiol. 2014;6:71-80.
Chey WD, Kurlander J, Eswaran S. Irritable bowel syndrome: a clinical review. JAMA. 2015;313:949-58.
Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical review on irritable bowel syndrome. Gastroenterology. 2002;123:2108-31.
El-Serag HB, Olden K, Bjorkman D. Health-related quality of life among persons with irritable bowel syndrome: a systematic review. Aliment Pharmacol Ter. 2002;16:1171-85.
Mayer EA. Clinical practice. Irritable bowel syndrome. N Engl J Med. 2008;358:1692-9.
Frank L, Kleinman L, Rentz A, Ciesla G, Kim JJ, Zacker C. Health-related quality of life associated with irritable bowel syndrome: comparison with other chronic diseases. Clin Ther. 2002;24:675-89.
Gralnek IM, Hays RD, Kilbourne A. The impact of irritable bowel syndrome on health-related quality of life. Gastroenterology. 2000;119:654-60.
Pace F, Molteni P, Bollani S, Sarzi-Puttini P, Stockbrügger R, Porro GB, et al. Inflammatory bowel disease versus irritable bowel syndrome: a hospital-based, case-control study of disease impact on quality of life. Scand J Gastroenterol. 2003;38:1031-8.
Lacy BE, Chey WD, Lembo AJ. New and emerging treatment options for irritable bowel syndrome. Gastroenterol Hepatol (N Y). 2015;11:1-19.
Lembo A. Irritable bowel syndrome medications side effects survey. J Clin Gastroenterol. 2004;38:776-81.
Quigley EM, Tack J, Chey WD, Rao SS, Fortea J, Falques M, et al. Randomised clinical trials: linaclotide phase 3 studies in IBS-C—a prespecified further analysis based on European Medicines Agency-specified endpoints. Aliment Pharmacol Ther. 2013;37:49-61.
Chey WD, Lembo AJ, Lavins BJ, Shiff SJ, Kurtz CB, Currie MG, et al. Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety. Am J Gastroenterol. 2012;107:1702-12.
Drossman DA, Chey WD, Johanson JF, Fass R, Scott C, Panas R, et al. Clinical trial: lubiprostone in patients with constipation-associated irritable bowel syndrome-results of two randomized, placebo-controlled studies. Aliment Pharmacol Ther. 2009;29:329-41.
Spencer AG, Labonte ED, Rosenbaum DP. Intestinal inhibition of the Na+/H+ exchanger 3 prevents cardiorenal damage in rats and inhibits Na+ uptake in humans. Sci Transl Med. 2014;6:227-36.
Johansson S, Rosenbaum DP, Knutsson M, Leonsson-Zachrisson M. A phase 1 study of the safety, tolerability, pharmacodynamics, and pharmacokinetics of tenapanor in healthy Japanese volunteers. Clin Exp Nephrol. 2017;21(3):407-16.
Eutamene H, Charmot D, Navre M, Bueno L. Visceral antinociceptive effects of RDX5791, a first-in-class minimally systemic NHE3 inhibitor on stress-induced colorectal hypersensitivity to distension in rats. Gastroenterology. 2011;140:S-57-8.
Zachos NC, Tse M, Donowotz M. Molecular Physiology of Instetine Na+/H +exchange. Annual review Physiol. 2005;67;411-43.
Charmot D. Non-systemic drugs: a critical review. Curr Pharm Des. 2012;18(10):1434-45.
Chey WD, Lembo AJ, Rosenbaum DP. Tenapanor Treatment of Patients With Constipation-Predominant Irritable Bowel Syndrome: A Phase 2, Randomized, Placebo-Controlled Efficacy and Safety Trial. Am J Gastroenterol. 2017;112(5):763-74.
Rosenbaum DP, Yan A, Jacobs JW. Pharmacodynamics, Safety, and Tolerability of the NHE3 Inhibitor Tenapanor: Two Trials in Healthy Volunteers. Clin Drug Investig. 2018;38(4):341-51.
Johansson S, Rosenbaum DP, Ahlqvist M, Rollison H, Knutsson M, Stefansson B, et al. Effects of Tenapanor on Cytochrome P450-Mediated Drug-Drug Interactions. Clin Pharmacol Drug Dev. 2017;6(5):466-75.
Johansson S, Rosenbaum D, Ahlqvist M, Rollison H, Knutsson M, Stefánsson B. Effects of Tenapanor on Cytochrome P450-Mediated Drug-Drug Interactions. Clin Pharmacol Drug Dev. 2017;6(5):466-75.
Brandsch M. Drug transport via the intestinal peptide transporter PepT1. Current Opinion Pharmacol. 2013;13(6):881-7.
Johansson S, Rosenbaum DP, Johan S, Bergur K, Mikael L, Eleanor H, et al. Tenapanor administration and the activity of the H + -coupled transporter PepT1 in healthy volunteers: Tenapanor and PepT1-mediated drug-drug interactions. Br J Clin Pharmacol. 2017.
Chey WD, Lembo AJ, Rosenbaum DP. Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 12-Week, Placebo-Controlled Phase 3 Trial (T3MPO-1). Am J Gastroenterol. 2020;115(2):281-93.
