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 Table of Contents  
REVIEW ARTICLE
Year : 2013  |  Volume : 27  |  Issue : 2  |  Page : 90-93

Linaclotide: A novel intestinal secretagogue for treating chronic constipation and constipation predominant irritable bowel syndrome


Department of Pharmacology, Dr. Harvansh Singh Judge Institute of Dental Sciences, Panjab University, Chandigarh, India

Date of Web Publication19-Nov-2013

Correspondence Address:
Ruchika Nandha
Department of Pharmacology, Dr. Harvansh Singh Judge Institute of Dental Sciences, Panjab University, Sector 25, Chandigarh - 160 014
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0972-4958.121571

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  Abstract 

Chronic constipation and constipation-predominant irritable bowel syndrome with constipation (IBS-C) are the common functional gastrointestinal problems which affect millions of people worldwide leading to increased health-care costs and impaired quality of life. Existing treatments have not been able to produce satisfactory results in 50% of the patient population. Drugs such as Tegaserod and Lubiprostone were also not clinically preferred because of cardiovascular adverse effects with the former and severe nausea causing intolerance with the later. Linaclotide is a first in class guanylate cyclase type-C receptor agonist, which has not only been found to be efficacious and safe for the treatment of chronic constipation and IBS-C but also has a positive impact on quality of life as demonstrated in placebo controlled clinical trials, with diarrhea as the most common adverse effect. This novel agent has recently been approved on 30 th August 2012 for clinical use in patients of more than 16 years of age.

Keywords: Chronic constipation, Irritable bowel syndrome, Linaclotide


How to cite this article:
Nandha R. Linaclotide: A novel intestinal secretagogue for treating chronic constipation and constipation predominant irritable bowel syndrome. J Med Soc 2013;27:90-3

How to cite this URL:
Nandha R. Linaclotide: A novel intestinal secretagogue for treating chronic constipation and constipation predominant irritable bowel syndrome. J Med Soc [serial online] 2013 [cited 2019 Dec 7];27:90-3. Available from: http://www.jmedsoc.org/text.asp?2013/27/2/90/121571


  Introduction Top


Chronic constipation and irritable bowel syndrome with constipation (IBS-C) are the most commonly reported functional gastrointestinal (GI) problems in today's scenario for which majority of the patients seek consultation of general practitioners and gastroenterologists. With an estimated prevalence of 20%, these GI conditions lead to impaired quality of life, associated co morbidities and huge economic burden. [1],[2],[3] Prevalence of chronic constipation has been estimated as 12-19%, which has a substantial impact on health-care costs and impaired quality of life. [4] Based on population-based studies, the overall prevalence of IBS is approximately 10-15% in United States (US) and 11.5% in Europe with negative economic impact directly through health-care utilization costs and indirectly through absenteeism from work. In US, estimated annual direct and indirect health-care costs due to IBS-C have been estimated to be as high as $30 billion. [4],[5]

Chronic constipation presents as infrequent bowel movements, hard stools, straining during defecation, bloating, abdominal discomfort, and a sense of incomplete evacuation. [6] In contrast, IBS is characterized by abdominal discomfort or cramping, exacerbating pain associated with defecation or a change in bowel habit ranging from diarrhea, constipation, alternating diarrhea and constipation, or normal bowel habits, alternating with either diarrhea and/or constipation. [4],[7] IBS-C is a subtype characterized mainly by abdominal pain and hard or lumpy stools at least 25% of the time and loose or watery stools less than 25% of the time. Constipation appears to be more prevalent in females, elderly, and patients of low socioeconomic strata. [1]

Treatment targets on improving bowel habits in chronic constipation and pain along with bowel movements in IBS-C. A variety of treatment options are available for the management of chronic constipation and IBS-C, but none has been found satisfactory by 50% of the sufferers. [2] Mainstay of treatment for constipation is symptomatic which includes dietary fibers or osmotic laxatives for constipation, low-dose antidepressants, hypnotherapy, psychotherapy or infrequent use of antispasmodics for pain, but all with limited evidence of their efficacy. [7]

Recent additions to this list include Tegaserod and Lubiprostone. Tegaserod, a 5-HT4 partial agonist, was approved in 2007 by US Food and Drug Administration (US FDA), but because of its propensity to cause cardiovascular events, it was withdrawn. Another approved drug, Lubiprostone, a chloride channel activator, given twice a day was found to be effective in the treatment of chronic constipation but because of higher incidence of nausea (29%), it was not preferred for the treatment of chronic constipation. [6] Hence lack of efficacy, safety or intolerance by the existing drugs demands for a novel molecule which is more efficacious, safe and tolerable too.

Linaclotide

Linaclotide, a chemical analogue of enterotoxin STa (causing pathogenic diarrhea) is an intestinal secretagogue, which has been found to improve the bowel habits and abdominal pain associated with chronic constipation and IBS-C. [4],[8],[9] This novel agent has recently been approved by US FDA on 30 th August, 2012 for treating chronic constipation and IBS-C.

Chemical Nature

Linaclotide is a first-in-class, orally administered 14-amino acid peptide [H-Cys 1 -Cys 2 -Glu 3 -Tyr 4 -Cys 5 -Cys 6 -Asn 7 -Pro 8 -Ala 9 -Cys 10 -Thr 11 -Gly 12 -Cys 13 -Tyr 14 -OH] with three sulphide bonds which make it stable. Its chemical formula is C 59 H 79 N 15 O 21 S 6 and molecular weight is 1526.74 gm/mol. It is converted to 13 amino acid peptide by carboxypeptidase enzyme to form an active metabolite MM-419447 by removal of C terminal tyrosine residue. [10]

Mechanism of Action

Being of the same family as guanylin and uroguanylin, It acts as an agonist of guanylate cyclase C resulting in a significant, concentration-dependent accumulation of intracellular cyclic guanosine-3', 5'-monophosphate (cGMP), which causes activation of cGMP dependent protein kinase resulting in phosphorylation of the cystic fibrosis transmembrane regulator (CFTR) through signal transduction cascade. CFTR is a chloride channel, which on the activation ultimately leads to increased intestinal secretions and GI transit by enhancing release of chloride and bicarbonate in the gut. Decreased visceral sensitivity has also been associated with high cGMP levels. [11],[12],[13]

Pharmacokinetics

Pharmacokinetic analysis of linaclotide showed minimal oral absorption and very low oral bioavailability (0.1%) due to rapid degradation. [13],[14] It is minimally cleared by hepatic and renal route so no dose adjustments are needed in hepatic or renal dysfunction. [15] In vitro mouse studies have demonstrated half-life of 3 min. Rat studies demonstrated stability of linaclotide in acidic medium as depicted from its stability after 3 h incubation in stimulated gastric fluid and complete resistance to hydrolysis by pepsin. [13] A significant, dose-dependent increase in GI transit rates in rats have been demonstrated with oral administration of ≥5 μg/kg linaclotide. [14]

Dosing

Linaclotide is available as oral capsule to be taken once a day 30 min before the first meal. Different doses in a range of 75 μcg to 1000 μcg have been studied for variable duration with the maximum of 26 weeks. Doses of 145 μcg and 290 μcg once daily for the treatment of chronic constipation and 266 μcg once daily for patients with IBS-C have been found to be effective and safe for further clinical use. [16],[17],[18]

Clinical Trials

Various clinical trials have been done to demonstrate significant and sustained efficacy as well as safety of linaclotide in patients with chronic constipation and IBS-C along with improvement in the quality of life providing such patients with a new option for the management when other treatments fail.

A pilot study was conducted in 42 patients with chronic constipation for 2 weeks by randomly assigning 100, 300, and 1000 μgm linaclotide or placebo once daily. Weekly range of continuous spontaneous bowel movements (CSBM) with three drug groups was 2.2-3.3 as compared to 1.3 with placebo. Stool consistency score and stool straining score as determined by 7 point scale in drug groups were 1.1-2.6 and 0.4-1.5 as compared to 0.4 and 0.4 for placebo group.100 μgm dose was sufficient to significantly improve spontaneous bowel movements (SBM) frequency whereas significant improvement in stool consistency was observed with 1000 μgm dose as compared to placebo (P < 0.05). [19]

Another dose range finding study was conducted at 57 clinical centers in US enrolling 310 patients with chronic constipation who were randomized to give oral linaclotide in doses of 75, 150,300 and 600 μgm or placebo once a day before the first meal of the day. Significant linear dose response trend was observed in increasing weekly SBM frequency with 2.6, 3.3, 3.6, and 4.3 (P value ≤ 0.0001) as compared to 1.5 for placebo with P value ≤ 0.05 for each dose versus placebo. [6]

Significant pharmacodynamic effect of linaclotide has also been demonstrated on GI transit and bowel functioning in 36 females suffering from IBS-C with 1000 μgm of linaclotide as compared to placebo without any significant difference in adverse effects. Linaclotide was also found to produce acceleration of time to first bowel movement, increase in stool frequency and decrease in stool consistency. [20]

In a randomized double blind, multicentred, placebo controlled study (n = 420), patients were randomized to give oral linaclotide in doses of 75, 150,300 and 600 μgm or placebo once a day for 12 weeks in patients suffering from IBS-C. Significant improvement was observed in bowel habits, frequency of SBM, CSBM, stool straining, stool consistency, abdominal discomfort, and bloating. Reduction in pain as measured by 5 point scale was −0.71,−0.71,−0.90,−0.80, and −0.49 respectively with 75, 150,300, and 600 μgm linaclotide and placebo with a significant difference from placebo. Incidence of diarrhea was found similar with study drug and placebo. [21]

Another randomized, double blind, placebo controlled 12 weeks study was conducted on 800 patients with IBS-C with oral once a day administration of 266 μgm of linaclotide (n = 405) or placebo (n = 395). Significant improvement was observed in primary and secondary end points after 1 week treatment with linaclotide, which was sustained without rebound constipation. 12.1% patients taking linaclotide experienced ≥30% reduction in CSBM, ≥3 CSBM per week and increase in ≥1 CSBM per week for at least 9 of 12 weeks as compared to 5.1% in the placebo group (P = 0.0004). Percentage of patients with ≥30% reduction in abdominal pain in 6 of 12 weeks was significantly higher with linaclotide use than placebo (50.1 vs. 37.5, P = 0.0003). Linaclotide withdrawal resulted in similar type of pain to the level of the placebo group in the treatment period, whereas switching over placebo patients to linaclotide led to improvement to the level of patients treated with linaclotide in 1 week. 5.7% patients in linaclotide group and 0.3% in the placebo group discontinued the treatment because of diarrhea. [16]

Similar phase three trial (n = 840) was carried out for 26 weeks by randomly assigning placebo to 403 and linaclotide 266 μgm in 401 patients with IBS-C demonstrating sustained and significant improvement in primary and secondary end points.12.7% patients taking linaclotide experienced ≥30% reduction in CSBM, ≥3 CSBM per week and increase in ≥1 CSBM per week for at least 9 of 12 weeks as compared to 3% in the placebo group (P ≤ 0.0001). Percentage of patients with ≥30% reduction in abdominal pain was significantly higher with linaclotide use than placebo (48.9 vs. 34.5, P ≤ 0.0001). Significant improvement was also demonstrated in secondary efficacy points such as abdominal discomfort, stool consistency, and straining. Diarrhea was the observed side-effect in 4% patients in linaclotide group and 0.2% patients in the placebo group. [17]

Two randomized, double blind, parallel group, placebo controlled trials (trial 303 and trial 01) were carried out including 1276 patients at 204 centers in US and 8 centers in Canada administrating dual doses of linaclotide 145 μgm and 290 μgm or placebo in patients suffering from chronic constipation. 21.2% patients in 145 μgm group and 19.4% in 240 μgm group had ≥3 CSBM per week as compared to 3.3% in the placebo group (P < 0.01). 16% patients in 145 μgm group and 21.3% in 240 μgm group had an increase in ≥1 CSBM per week for at least 9 of 12 weeks as compared to 6.0% in the placebo group (P < 0.01). In trial 303, after treatment completion, in 4 week randomized withdrawal period, decreased rate of in CSBM was observed in patients who were randomly assigned placebo after receiving linaclotide during the preceding 12-week treatment period and increase in CSBM was recorded in patients who were assigned to 290 μg of linaclotide after treatment with placebo. Discontinuation of treatment due to diarrhea was higher in the linaclotide-treated groups (7.9% linaclotide 145 mcg, 7.3% linaclotide 290 mcg, and 4.3% placebo) with no evidence of rebound constipation. [18]

Linaclotide has also been shown to improve the quality of life in patients of chronic constipation and IBS-C along with the multisymptom relief. In a study enrolling1490 patients, patients were randomized to receive linaclotide 266 μcg (n = 748) or placebo (n = 742) for 12 weeks. At week 12, patients who received linaclotide had a significantly higher mean change in their overall IBS-quality of life score (by 34 item, 5 point response scale) from baseline compared with the placebo group (+17.45 and +13.10, respectively; P < 0.0001). [22]

Adverse Drug Reactions

Diarrhoea has been reported as most common adverse effect with linaclotide treatment in chronic constipation and IBS-C patients which is more at higher doses. [6],[16],[17],[18],[19],[20],[21] Other gastrointestinal tract (GIT) related adverse effects are flatulence and abdominal distension. No rebound constipation has been observed with linaclotide use showing its sustained action. Chances of drug interactions are low because of its low absorption, rapid degradation and its local action in GIT. [13] Its use has been restricted under 16 years of age.

In conclusion, linaclotide has been found to not only treat IBS-C and chronic constipation efficaciously and safely without rebound constipation, it has also been found to demonstrate the positive impact on quality of life of such patients. Other points which go in favor of its use are reduction in abdominal pain, mild systemic absorption, no dose adjustment in renal or hepatic patients, no drug interactions and ability to alleviate symptoms with once daily dosing. Pharmacoeconomics studies demonstrating the cost benefit ratio with this novel agent are lacking. Placebo controlled studies though provide substantial data to ascertain its superiority but lack of comparative studies with the already existing drugs raises a question mark on its superiority over the existing remedies. Till now this attractive drug can be categorized under second tier agents used in IBS-C and chronic constipation along with lubiprostone. Hence to practically mark this remedy as a better option, head to head comparative clinical trials with the conventional treatment strategies are warranted in future.

 
  References Top

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11.Bryant AP, Busby RW, Bartolini WP, Cordero EA, Hannig G, Kessler MM, et al. Linaclotide is a potent and selective guanylate cyclase C agonist that elicits pharmacological effects locally in the gastrointestinal tract. Life Sci 2010;86:760-5.  Back to cited text no. 11
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12.Eutamene H, Bradesi S, Larauche M, Theodorou V, Beaufrand C, Ohning G, et al. Guanylate cyclase C-mediated antinociceptive effects of linaclotide in rodent models of visceral pain. Neurogastroenterol Motil 2010;22:312-e84.  Back to cited text no. 12
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14.Busby RW, Bryant AP, Bartolini WP, Cordero EA, Hannig G, Kessler MM, et al. Linaclotide, through activation of guanylate cyclase C, acts locally in the gastrointestinal tract to elicit enhanced intestinal secretion and transit. Eur J Pharmacol 2010;649:328-35.  Back to cited text no. 14
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16.Rao S, Lembo A, Shiff SJ, Shi K, Johnston JM, Schneier H. Efficacy and safety of once daily linaclotide in patients with irritable bowel syndrome with constipation: A 12-week, randomized, double-blind, placebo-controlled phase 3 trial followed by a 4-week randomized withdrawal period. Gastroenterology [AGA abstract 845] 2011;140:S138.  Back to cited text no. 16
    
17.Chey WD, Lembo A, MacDougall JE, Lavins BJ, Schneier H, Johnston JM. Efficacy and safety of once-daily linaclotide administered orally for 26 weeks in patients with IBS-C: results from a randomized, double-blind, placebo-controlled phase 3 trial. Gastroenterology [AGA abstract 837] 2011;140:S135.  Back to cited text no. 17
    
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22.Carson R, Tourkodimitris S, Lewis BE, Johnston JM. Effect of linaclotide on quality of life in adults with irritable bowel syndrome with constipation: pooled results from two randomized, double-blind, placebo-controlled phase 3 trials. Gastroenterology [AGA abstract 223] 2011;140:S51.  Back to cited text no. 22
    




 

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