Plecanatide

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Plecanatide
Plecanatide sequence.svg
Clinical data
Trade names Trulance
Other namesSP-304
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C65H104N18O26S4
Molar mass 1681.89 g·mol−1
3D model (JSmol)
  • CC1C(=O)NC2CSSCC(C(=O)NC(C(=O)NC(C(=O)NC(CSSCC(NC(=O)CNC(=O)C(NC2=O)C(C)O)C(=O)NC(CC(C)C)C(=O)O)C(=O)NC(C(=O)NC(C(=O)NC(C(=O)N1)C(C)C)CC(=O)N)C(C)C)CC(C)C)CCC(=O)O)NC(=O)C(CCC(=O)O)NC(=O)C(CC(=O)O)NC(=O)C(CC(=O)N)N
  • InChI=1S/C65H104N18O26S4/c1-25(2)15-34-55(98)80-41-24-113-110-21-38(58(101)77-37(65(108)109)16-26(3)4)71-44(87)20-69-62(105)50(30(10)84)83-61(104)40(78-51(94)29(9)70-63(106)48(27(5)6)81-57(100)35(18-43(68)86)76-64(107)49(28(7)8)82-60(41)103)23-112-111-22-39(59(102)73-32(53(96)75-34)11-13-45(88)89)79-54(97)33(12-14-46(90)91)72-56(99)36(19-47(92)93)74-52(95)31(66)17-42(67)85/h25-41,48-50,84H,11-24,66H2,1-10H3,(H2,67,85)(H2,68,86)(H,69,105)(H,70,106)(H,71,87)(H,72,99)(H,73,102)(H,74,95)(H,75,96)(H,76,107)(H,77,101)(H,78,94)(H,79,97)(H,80,98)(H,81,100)(H,82,103)(H,83,104)(H,88,89)(H,90,91)(H,92,93)(H,108,109)/t29-,30+,31-,32-,33-,34-,35-,36-,37-,38-,39-,40-,41-,48-,49-,50-/m0/s1 X mark.svgN
  • Key:NSPHQWLKCGGCQR-DLJDZFDSSA-N X mark.svgN

Plecanatide, sold under the brand name Trulance, is a medication for the treatment of chronic idiopathic constipation (CIC) [3] and irritable bowel syndrome with constipation. [4] It is being launched in India under the brand name "Plecasoft" (Gromaxx, Zuventus Health care ltd, India). Plecanatide is an agonist of guanylate cyclase-C. Plecanatide increases intestinal transit and fluid through a buildup of cGMP. [5] [6]

Contents

Chemistry

Plecanatide, a 16-amino acid peptide structurally identical to human uroguanylin (with exception of a single-amino acid substitution. Plecanatide is a guanylate cyclase-C (GC-C) agonist.

Molecular weight: 1682 Daltons

Structural formula: C65H104N18O26S4

Chemical name: L-Leucine, L-asparaginyl-L-α-aspartyl-L-α-glutamyl-L-cysteinyl-L-αglutamyl-L-leucyl-L-cysteinyl-L-valyl-L-asparaginyl-L-valyl-L-alanyl-L-cysteinyl-L-threonylglycyl-Lcysteinyl-, cyclic (4→12),(7→15)-bis(disulfide). [7]

Medical uses

As of January 2017, plecanatide is approved in the United States for the treatment of chronic idiopathic constipation in adults. [3] later it was also approved for irritable bowel syndrome with constipation (IBS-C). [8]

The presence of this condition is determined using the Rome III diagnostic criteria for chronic constipation which requires that the patient meet stool frequency, stool consistency, incomplete evacuation, and straining requirements in addition to not being a likely candidate for irritable bowel syndrome. [4] [9] The symptoms should also have been present for at least three of the last six months to establish the chronic nature of the condition before treatment with plecanatide is indicated. [9]

Plecanatide has been shown to be safe and effective. It has shown to be at least equally as effective as its main competitor, linaclotide (brand name Linzess), but has been shown to have a lower rate of diarrhea as an adverse drug reaction. [10]

Dosage and Administration

The recommended dosage of plecanatide is 3 mg taken by mouth once daily. [8] [11]

A plecanatide tablet can be taken with or without food and should be swallowed whole. For adults with swallowing difficulties, plecanatide tablets can be crushed and administered orally either in apple sauce or with water or administered with water via a nasogastric or gastric feeding tube. [11]

Contraindications

Plecanatide has not been shown to be safe or effective in persons 6 years to 18 years of age. [12] Use of plecanatide by persons under the age of 6 poses a serious dehydration risk and studies have demonstrated plecanatide can cause death in juvenile mice due to this dehydrating effect. [12]

Use of plecanatide is also contraindicated in persons who are suspected of having a mechanical gastrointestinal obstruction. [12]

Pharmacology

Structure and function

Plecanatide is a 16 amino acid peptide with the amino acid sequence:

H-Asn1-Asp2-Glu3-Cys4-Glu5-Leu6-Cys7-Val8-Asn9-Val10-Ala11-Cys12-Thr13-Gly14-Cys15-Leu16-OH

(one-letter sequence: NDECELCVNVACTGCL). Plecanatide is nearly structurally identical to human uroguanylin, apart from the substitution of Asp3 with Glu3. [13] Disulfide bonds exist between Cys4 and Cys12, as well as Cys7 and Cys15. [14]

Plecanatide has two important motifs. The first being the acidic residues Asp2 and Glu3 which modulate the affinity for its receptor in response to environmental pH. [12] [13] [15] Simulations predict the optimal activity of Plecanatide to occur at pH 5, making it suitable for targeting cells within the proximal intestine, which has a pH of between 5 and 6. [12] The second is the ACTGC motif (residues Ala11 to Cys15) which is the region responsible for its binding to the receptor, guanylate cyclase-C. [16]

Mechanism of action

Plecanatide works as a laxative by drawing water in to the gastrointestinal tract thereby softening stool and encouraging its natural passage.

Similar to its endogenous counterpart, plecanatide activates guanylate cyclase-C on endothelial cells within the gastrointestinal tract. [13] The activation of guanylate cyclase-C catalyses the production of the second messenger guanosine 3’,5’-cyclic monophosphate (cGMP) which leads to the protein kinase A (PKA) and protein kinase G II (PKGII)-mediated phosphorylation of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. [17] [18] CFTR is an anion channel and upon activation it will secrete negatively charged ions, particularly chloride (Cl−) and bicarbonate (HCO3−) in to the GI tract lumen. [19] [20] This disruption to the electrochemical gradient is in part rectified by the passive secretion of positively charged sodium ions in to the lumen and water follows by osmosis. [19]

Plecanatide is also known to have an anti-nociceptive effect in animal models, however the exact mechanism of action is not yet fully elucidated. [12] It has been suggested that this may be in part to the anti-inflammatory action of guanylate cyclase-C by its inhibition of pro-inflammatory cytokines, or through the inhibition of associated sensory neurons. [21]

Pharmacokinetics and metabolism

As plecanatide acts on receptors present on the apical side of endothelial cells lining the gastrointestinal tract it is able to impart its effect without ever entering circulation. [13] As with most orally ingested peptides, plecanatide is degraded by intestinal enzymes, and so very little of the active drug enters systemic circulation. [12] Minimal amounts of the drug are expected to be transported in to the body, and concentrations of plecanatide and its metabolites are undetectable in plasma following the recommended dosage of 3 mg. [12] [13] It has also been shown that dosages up to 48.6 mg produced no detectable concentration of plecanatide in human plasma at any time point after ingestion. [13]

Related Research Articles

<span class="mw-page-title-main">Small intestine</span> Organ in the gastrointestinal tract

The small intestine or small bowel is an organ in the gastrointestinal tract where most of the absorption of nutrients from food takes place. It lies between the stomach and large intestine, and receives bile and pancreatic juice through the pancreatic duct to aid in digestion. The small intestine is about 5.5 metres long and folds many times to fit in the abdomen. Although it is longer than the large intestine, it is called the small intestine because it is narrower in diameter.

<span class="mw-page-title-main">Laxative</span> Agents that relax and loosen the bowels and stools

Laxatives, purgatives, or aperients are substances that loosen stools and increase bowel movements. They are used to treat and prevent constipation.

<span class="mw-page-title-main">Irritable bowel syndrome</span> Functional gastrointestinal disorder

Irritable bowel syndrome (IBS) is a "disorder of gut-brain interaction" characterized by a group of symptoms that commonly include abdominal pain, abdominal bloating and changes in the consistency of bowel movements. These symptoms may occur over a long time, sometimes for years. IBS can negatively affect quality of life and may result in missed school or work or reduced productivity at work. Disorders such as anxiety, major depression, and chronic fatigue syndrome are common among people with IBS.

Functional gastrointestinal disorders (FGID), also known as disorders of gut–brain interaction, include a number of separate idiopathic disorders which affect different parts of the gastrointestinal tract and involve visceral hypersensitivity and motility disturbances.

Functional constipation, known as chronic idiopathic constipation (CIC), is constipation that does not have a physical (anatomical) or physiological cause. It may have a neurological, psychological or psychosomatic cause. A person with functional constipation may be healthy, yet has difficulty defecating.

<span class="mw-page-title-main">Achlorhydria</span> Medical condition

Achlorhydria and hypochlorhydria refer to states where the production of hydrochloric acid in gastric secretions of the stomach and other digestive organs is absent or low, respectively. It is associated with various other medical problems.

<span class="mw-page-title-main">Gastrointestinal disease</span> Medical condition

Gastrointestinal diseases refer to diseases involving the gastrointestinal tract, namely the esophagus, stomach, small intestine, large intestine and rectum, and the accessory organs of digestion, the liver, gallbladder, and pancreas.

<span class="mw-page-title-main">Alosetron</span> Medication

Alosetron, sold under the brand name Lotronex among others, is a 5-HT3 antagonist used for the management of severe diarrhea-predominant irritable bowel syndrome (IBS) in females only.

<span class="mw-page-title-main">Tegaserod</span> Medication

Tegaserod is a 5-HT4 agonist manufactured by Novartis and sold under the names Zelnorm and Zelmac for the management of irritable bowel syndrome and constipation. Approved by the FDA in 2002, it was subsequently removed from the market in 2007 due to FDA concerns about possible adverse cardiovascular effects. Before then, it was the only drug approved by the United States Food and Drug Administration to help relieve the abdominal discomfort, bloating, and constipation associated with irritable bowel syndrome. Its use was also approved to treat chronic idiopathic constipation.

<span class="mw-page-title-main">Colestyramine</span> Pharmaceutical drug

Colestyramine (INN) or cholestyramine (USAN) is a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption. It is a strong ion exchange resin, which means it can exchange its chloride anions with anionic bile acids in the gastrointestinal tract and bind them strongly in the resin matrix. The functional group of the anion exchange resin is a quaternary ammonium group attached to an inert styrene-divinylbenzene copolymer.

<span class="mw-page-title-main">Enterochromaffin cell</span> Cell type

Enterochromaffin (EC) cells are a type of enteroendocrine cell, and neuroendocrine cell. They reside alongside the epithelium lining the lumen of the digestive tract and play a crucial role in gastrointestinal regulation, particularly intestinal motility and secretion. They were discovered by Nikolai Kulchitsky.

<span class="mw-page-title-main">Rifaximin</span> Antibiotic medication

Rifaximin, is a non-absorbable, broad spectrum antibiotic mainly used to treat travelers' diarrhea. It is based on the rifamycin antibiotics family. Since its approval in Italy in 1987, it has been licensed in over more than 30 countries for the treatment of a variety of gastrointestinal diseases like irritable bowel syndrome, and hepatic encephalopathy. It acts by inhibiting RNA synthesis in susceptible bacteria by binding to the RNA polymerase enzyme. This binding blocks translocation, which stops transcription. It is marketed under the brand name Xifaxan by Salix Pharmaceuticals.

<span class="mw-page-title-main">Lubiprostone</span> Medication used for constipation

Lubiprostone, sold under the brand name Amitiza among others, is a medication used in the management of chronic idiopathic constipation, predominantly irritable bowel syndrome-associated constipation in women and opioid-induced constipation. The drug is owned by Mallinckrodt and is marketed by Takeda Pharmaceutical Company.

<span class="mw-page-title-main">Prucalopride</span> Drug used to treat chronic constipation

Prucalopride, sold under brand names Resolor and Motegrity among others, is a medication acting as a selective, high affinity 5-HT4 receptor agonist which targets the impaired motility associated with chronic constipation, thus normalizing bowel movements. Prucalopride was approved for medical use in the European Union in 2009, in Canada in 2011, in Israel in 2014, and in the United States in December 2018. The drug has also been tested for the treatment of chronic intestinal pseudo-obstruction.

A prokinetic agent is a type of small peptide drug which enhances gastrointestinal motility by increasing the frequency or strength of contractions, but without disrupting their rhythm. They are used to treat certain gastrointestinal symptoms, including abdominal discomfort, bloating, constipation, heart burn, nausea, and vomiting; and certain gastrointestinal disorders, including irritable bowel syndrome, gastritis, gastroparesis, and functional dyspepsia.

<span class="mw-page-title-main">Linaclotide</span> Medicine

Linaclotide, is a drug used to treat irritable bowel syndrome with constipation and chronic constipation with no known cause. It has a black box warning about the risk of serious dehydration in children in the US; the most common adverse effects in others include diarrhea.

Bile acid malabsorption (BAM), known also as bile acid diarrhea, is a cause of several gut-related problems, the main one being chronic diarrhea. It has also been called bile acid-induced diarrhea, cholerheic or choleretic enteropathy, bile salt diarrhea or bile salt malabsorption. It can result from malabsorption secondary to gastrointestinal disease, or be a primary disorder, associated with excessive bile acid production. Treatment with bile acid sequestrants is often effective. It is recognised as a disability in the United Kingdom under the Equality Act 2010

<span class="mw-page-title-main">Velusetrag</span> Chemical compound

Velusetrag (INN, USAN; previously known as TD-5108) is an experimental drug candidate for the treatment of gastric neuromuscular disorders including gastroparesis, and lower gastrointestinal motility disorders including chronic idiopathic constipation and irritable bowel syndrome. It is a potent, selective, high efficacy 5-HT4 receptor serotonin agonist being developed by Theravance Biopharma and Alfa Wassermann. Velusetrag demonstrates less selectivity for other serotonin receptors, such as 5-HT2 and 5-HT3, to earlier generation 5-HT agonists like cisapride and tegaserod.

<span class="mw-page-title-main">Elobixibat</span> Chemical compound

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Serum-derived bovine immunoglobulin/protein isolate (SBI) is a medical food product derived from bovine serum obtained from adult cows in the United States. It is sold under the name EnteraGam.

References

  1. ↑ "Summary Basis of Decision (SBD) for Trulance". Health Canada . 23 October 2014. Retrieved 29 May 2022.
  2. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 Oct 2023.
  3. 1 2 "FDA approves Trulance for Chronic Idiopathic Constipation". FDA.gov. U.S. Food and Drug Administration. Retrieved 20 January 2017.
  4. 1 2 Miner, Philip B (2020-02-01). "Plecanatide for the treatment of constipation-predominant irritable bowel syndrome". Expert Review of Gastroenterology & Hepatology. 14 (2): 71–84. doi:10.1080/17474124.2020.1722101. ISSN   1747-4124. PMID   31985305. S2CID   210922857.
  5. ↑ "TRULANCE package insert" (PDF). Trulance website. Synergy Pharmaceuticals Inc. 420 Lexington Avenue, Suite 2012 New York, New York 10170. Retrieved 20 January 2017.
  6. ↑ Thomas RH, Luthin DR (June 2015). "Current and emerging treatments for irritable bowel syndrome with constipation and chronic idiopathic constipation: focus on prosecretory agents". Pharmacotherapy. 35 (6): 613–30. doi:10.1002/phar.1594. PMID   26016701. S2CID   24825251.
  7. ↑ "TRULANCE (plecanatide) tablets, for oral use" (PDF). Synergy Pharmaceuticals Inc. U.S. Food and Drug Administration. January 2017.
  8. 1 2 "TRULANCE (plecanatide) tablets, for oral use" (PDF). Synergy Pharmaceuticals Inc. U.S. Food and Drug Administration. January 2017.
  9. 1 2 Drossman DA (2006). Rome III: the functional gastrointestinal disorders (3rd ed.). McLean, Va.: Degnon Associates. ISBN   9780965683753. OCLC   79476570.
  10. ↑ "Trulance - FDA prescribing information, side effects and uses". Drugs.com. Retrieved 2017-10-27.
  11. 1 2 Kamuda JA, Mazzola N (April 2018). "Plecanatide (Trulance) for Chronic Idiopathic Constipation and Irritable Bowel Syndrome With Constipation". P & T: A Peer-Reviewed Journal for Formulary Management. 43 (4): 207–232. PMC   5871240 . PMID   29622940.
  12. 1 2 3 4 5 6 7 8 Al-Salama ZT, Syed YY (April 2017). "Plecanatide: First Global Approval". Drugs. 77 (5): 593–598. doi:10.1007/s40265-017-0718-0. PMID   28255961. S2CID   29735532.
  13. 1 2 3 4 5 6 Shailubhai K, Comiskey S, Foss JA, Feng R, Barrow L, Comer GM, Jacob GS (September 2013). "Plecanatide, an oral guanylate cyclase C agonist acting locally in the gastrointestinal tract, is safe and well-tolerated in single doses". Digestive Diseases and Sciences. 58 (9): 2580–6. doi:10.1007/s10620-013-2684-z. PMID   23625291. S2CID   10123241.
  14. ↑ Chang WL, Masih S, Thadi A, Patwa V, Joshi A, Cooper HS, et al. (February 2017). "+/Min-FCCC mice". World Journal of Gastrointestinal Pharmacology and Therapeutics. 8 (1): 47–59. doi: 10.4292/wjgpt.v8.i1.47 . PMC   5292606 . PMID   28217374.
  15. ↑ Hamra FK, Eber SL, Chin DT, Currie MG, Forte LR (March 1997). "Regulation of intestinal uroguanylin/guanylin receptor-mediated responses by mucosal acidity". Proceedings of the National Academy of Sciences of the United States of America. 94 (6): 2705–10. Bibcode:1997PNAS...94.2705H. doi: 10.1073/pnas.94.6.2705 . PMC   20153 . PMID   9122260.
  16. ↑ Forte LR (November 2004). "Uroguanylin and guanylin peptides: pharmacology and experimental therapeutics". Pharmacology & Therapeutics. 104 (2): 137–62. doi:10.1016/j.pharmthera.2004.08.007. PMID   15518884.
  17. ↑ Hamra FK, Forte LR, Eber SL, Pidhorodeckyj NV, Krause WJ, Freeman RH, et al. (November 1993). "Uroguanylin: structure and activity of a second endogenous peptide that stimulates intestinal guanylate cyclase". Proceedings of the National Academy of Sciences of the United States of America. 90 (22): 10464–8. Bibcode:1993PNAS...9010464H. doi: 10.1073/pnas.90.22.10464 . PMC   47797 . PMID   7902563.
  18. ↑ Bijvelds MJ, Loos M, Bronsveld I, Hellemans A, Bongartz JP, Ver Donck L, et al. (December 2015). "Inhibition of Heat-Stable Toxin-Induced Intestinal Salt and Water Secretion by a Novel Class of Guanylyl Cyclase C Inhibitors". The Journal of Infectious Diseases. 212 (11): 1806–15. doi: 10.1093/infdis/jiv300 . PMID   25999056.
  19. 1 2 Gadsby DC, Vergani P, Csanády L (March 2006). "The ABC protein turned chloride channel whose failure causes cystic fibrosis". Nature. 440 (7083): 477–83. Bibcode:2006Natur.440..477G. doi:10.1038/nature04712. PMC   2720541 . PMID   16554808.
  20. ↑ Park HW, Nam JH, Kim JY, Namkung W, Yoon JS, Lee JS, et al. (August 2010). "Dynamic regulation of CFTR bicarbonate permeability by [Cl-]i and its role in pancreatic bicarbonate secretion". Gastroenterology. 139 (2): 620–31. doi:10.1053/j.gastro.2010.04.004. PMID   20398666.
  21. ↑ Eutamene H, Bradesi S, Larauche M, Theodorou V, Beaufrand C, Ohning G, et al. (March 2010). "Guanylate cyclase C-mediated antinociceptive effects of linaclotide in rodent models of visceral pain". Neurogastroenterology and Motility. 22 (3): 312–e84. doi:10.1111/j.1365-2982.2009.01385.x. PMID   19706070. S2CID   9190733.
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