Continuing Education Activity

Linaclotide is a medication used to manage and treat constipation associated with functional gastrointestinal disorders. It is in the guanylate cyclase-C receptors agonist class of drugs. This activity describes the indications, mechanism of action, contraindications, adverse event profile, and other key factors (e.g., dosing, pharmacodynamics, pharmacokinetics, counseling of patients) pertinent for members of the interprofessional team in the management of patients suffering from irritable bowel syndrome with predominant constipation and chronic idiopathic syndrome.

Objectives:

• Identify the common indications for linaclotide therapy.
• Explain the unique mechanism of linaclotide’s pharmacological action.
• Describe the most frequently encountered adverse events associated with linaclotide therapy.
• Review the most common contraindications for linaclotide treatment.

Indications

Linaclotide is an orally administered medication with a once-a-day dosage regimen and a first-in-class, potent, and highly selective agonist of guanylate cyclase-C (GC-C) receptors in the inner lining of the intestine. This therapeutic peptide has negligible bioavailability following oral administration and a favorable safety profile. In the USA, the FDA approved it on 30th August 2012 for the treatment of adults suffering from the following medical conditions.

• Irritable bowel syndrome with predominant constipation(IBS-C).[1][2][3]
• Chronic idiopathic constipation(CIC).[4][5]         

Non-FDA-Approved Indications

Linaclotide can be used to manage refractory lower gastrointestinal manifestations in patients with systemic sclerosis. A low dose of linaclotide is an effective regimen and might be better tolerated, but a subset of patients may need a high dosage.[6]

• Constipation induced by drugs such as opioids, calcium channel blockers, etc. Linaclotide significantly improves opioid-induced constipation symptoms of stool consistency, straining, abdominal bloating, and treatment satisfaction score in patients with chronic noncancer pain.[7] 
• Diabetes mellitus with chronic constipation
• Constipation due to neurological conditions such as stroke, Parkinson disease, brain or spinal cord injuries, multiple sclerosis, or weak pelvic floor muscles
• Constipation after surgery
• Hemorrhoids 
• Anal fissure

The following studies have provided a rationale for the potential therapeutic development of linaclotide:

In animal studies, activation of guanylate cyclase 2C receptors located in the mediobasal hypothalamic region by orally administered linaclotide stimulates the sympathetic nervous system leading to thermogenesis of brown fat, causing increased energy expenditure and ultimately, loss of body weight without dietary modification.[8]

Linaclotide inhibits the absorption of sodium, leading to fluid retention and increased fluidity of intestinal contents, improving gastrointestinal transit in cystic fibrosis model of mice carrying either deltaF508 or null mutations by inhibiting sodium/hydrogen exchanger 3.[9]

According to an emerging paradigm, guanylate cyclase C (GUCY2C) behaves as a tumor suppressor in the intestine, and the loss of endogenous hormone ligands for GC-C receptor results in dysfunction of mucosal cells, and this represents an important step in the pathogenesis of the disease. In this context, replacement therapy with GUCY2C ligand has been proposed as a strategy for preventing colorectal cancer, a translational opportunity for linaclotide.[10]

Linaclotide decreased trimethylamine-N-oxide (TMAO), a hepatic metabolic product of trimethylamine derived from dietary phosphatidylcholine or carnitine generated by microbiota. TMAO has been directly associated with the progression of cardiovascular diseases and the dysfunction of kidneys. Therefore, linaclotide could be used as a powerful tool for preventing and controlling cardiorenal syndrome by ameliorating the gut-cardio-renal axis.[11]

A wealth of studies indicates that guanylate cyclase plays a multitude of diverse additional protective roles in the barrier function of the mucosa and tissue injury and inflammation besides cell proliferation and apoptosis. Signaling from the recently identified extraintestinal GC-C pathways contributes to food intake regulation and symptoms linked with attention deficit hyperactivity disorder.[12] All of these provide future therapeutic potential for linaclotide within and outside of the gastrointestinal tract.

Mechanism of Action

Chemically, linaclotide is a small, synthetic, and heterodetic cyclic peptide made of 14-amino acids with interlinking three disulfide bonds. In this molecule, from right to left, the sequence of amino acids is L-cysteinyl-L-cysteinyl-L-glutamyl-L-tyrosyl-L- cysteinyl-L-cysteinyl-L-asparaginyl-L-prolyl-L-alanyl-L-cysteinyl-L-threonyl-glycyl-L-cysteinyl-L- tyrosine with cyclic between amino acids (1-6), (2-10), and (5-13)-tris (disulfide).

Linaclotide's molecular formula is C59H79N15O21S6 and has a molecular weight of 1526.8. Linaclotide is an amorphous substance, white to off-white colored powder. It is sparingly soluble in water and aqueous 0.9% sodium chloride.

Mechanism of Action

Linaclotide, a promising drug, is structurally similar to human endogenous hormones guanylin and uroguanylin and functionally analogous to heat-stable enterotoxin of pathogenic strains of Escherichia coli organisms. Linaclotide acts as a potent and highly selective agonist of guanylate cyclase-2C (GC-2C).[13][14][15] Linaclotide and its active metabolites bind to transmembrane GC-C receptors and function locally on the luminal surface of the mucosa, the epithelial lining of the intestine.[16] 

The activation of GC-C causes elevated intracellular and extracellular cyclic guanosine monophosphate (cGMP) levels. Increased concentration of intracellular cGMP stimulates the secretion of electrolytes, chloride, and bicarbonate, into the lumen of the intestine, mainly via activation of the ion channel called cystic fibrosis transmembrane conductance regulator (CFTR) and inhibits the absorption of sodium, resulting in increased intestinal fluid content and accelerated transit.

Linaclotide has a novel dual mode of action. Increased levels of extracellular cGMP in submucosa inhibit colonic nociceptors and relieve abdominal pain.[17] Inhibition of colonic afferent nociception by linaclotide treatment in IBS-C reverses the neuroplasticity, which normalizes the extraintestinal morbidities, including persistent bladder dysfunction, which includes the overactive bladder and interstitial cystitis/painful bladder syndrome.[18]

In an animal model of visceral pain, linaclotide also reduces the contraction of abdominal muscles.

As per the results of animal studies and clinical trials, linaclotide improves constipation and various abdominal symptoms and the quality of life (QOL) in patients suffering from irritable bowel syndrome with predominant constipation and chronic idiopathic constipation.[19][20] Moreover, linaclotide has a favorable safety profile, and resistance to linaclotide was not observed during clinical trials, unlike some of the other approved therapeutic agents.[21]

Linaclotide can be effectively combined with other therapeutic agents to treat refractory constipation.[14]

Pharmacodynamics

Food Effects

In clinical trials, linaclotide was taken on an empty stomach, at least half an hour before the breakfast. Administering the linaclotide immediately after the breakfast rich in fat resulted in stool with looser consistency and a higher frequency of stool compared to taking it in the fasted state.

Pharmacokinetics

Absorption

Linaclotide is minimally absorbed with negligible bioavailability after oral administration. Plasma concentrations of linaclotide and its active metabolites are below the measurable level following oral ingestion of 145 mcg and 290 mcg doses. Therefore, calculation of standard pharmacokinetic parameters such as AUC (area under the curve), Cmax (maximum concentration), and t½ (half-life) cannot be performed.

Food Effect

In a clinical trial, neither linaclotide nor its active metabolite MM-419447 was detected in plasma after oral intake of 290 mcg once a day dosage for seven days in both fed and non-fed states in healthy volunteers.

Distribution

Given that the concentration of linaclotide in the plasma following oral administration of the recommended doses is not quantifiable, the distribution of linaclotide to tissues in organ systems to any clinically relevant extent is not expected.

Elimination

Metabolism

Linaclotide is metabolized in the gastrointestinal tract (GI). It is stable in the acidic (low pH) environment of the stomach. By loss of terminal tyrosine moiety in the small intestine, linaclotide is metabolized to its principal and active metabolite MM-419447 (CCEYCCNPACTGC), which contributes to pharmacological effects of the parent drug linaclotide. The systemic exposure to active peptides is minimal. In addition, low systemic and portal vein concentration of both linaclotide and metabolites confirms poor bioavailability when administered orally. The reduction of disulfide bonds of both peptides takes place in the small intestine, where subsequently, they are proteolyzed and degraded into smaller peptides and naturally occurring amino acids.[22]

Following oral administration, linaclotide metabolizes within one hour in the gastrointestinal tract. Due to its high susceptibility to proteolytic degradation, linaclotide or its active metabolite has limited therapeutic application. The linaclotide analogs, the next generation of potent peptides with enhanced stability in the gut, might improve the therapeutic utility.

Excretion

In fed and fasted healthy subjects, following oral administration of linaclotide 290 mcg once a day dosage for a week, a mean of 3% (fed) and 5% (fasted) of the dose was excreted as an active peptide in the feces and an active metabolite MM-419447 was the predominant peptide recovered.

In vitro studies, MM-419447 binds to T84 cells with high affinity, which results in remarkable concentration-dependent intracellular accumulation of cyclic guanosine-3',5'-monophosphate (cGMP). In animal studies, orally dosed MM-419447 increased intraluminal cGMP, significantly increased fluid secretion into the loops of the small bowel, and caused a dose-dependent acceleration of GI transit. These results demonstrate that the active metabolite plays an important role in contributing to linaclotide's pharmacology.

Drug Interaction Studies

Clinical studies for drug-to-drug interactions have not been conducted with linaclotide. In addition, systemic absorption of the linaclotide and its active metabolite is minimal after orally administered drug dosages.

According to the results of in vitro studies, linaclotide does not interact with the cytochrome P450 enzyme system. Also, linaclotide does not interact with the uptake and efflux (including the P-glycoprotein(P-gp)) transporters. As per these in vitro data, no interactions of linaclotide with other drugs are anticipated by modulation of CYP enzymes or common transporters.

Use and Risk Summary in Specific Populations

Renal and Hepatic Impairment

Renal and hepatic dysfunction is not expected to affect the elimination of linaclotide or its active metabolite as linaclotide metabolism takes place within the gastrointestinal tract and linaclotide concentrations in plasma are below the quantitation limit following oral administration of the recommended dosage.

Pregnancy

In animal developmental studies, no effects were observed on developing embryos and fetuses following oral administration of linaclotide during the organogenesis phase in rats and rabbits at much higher doses than the maximum recommended dosage for the human species. The association between severe maternal toxicity and effects on fetal morphology existed in mice. The estimated background risk for major congenital defects and miscarriage is unknown for the indicated patient population.

Systemic absorption of linaclotide and its active metabolite MM-419447 is negligible after dosing orally. Therefore, use by gravid mothers is not anticipated to cause any drug exposure to embryos and fetuses. However, the available data on linaclotide use in pregnant females is inadequate to draw a conclusion regarding the drug-related risk of fetal malformation and abortion.

Lactation

Linaclotide and its metabolite were not discovered in human milk. In adults, the plasma concentration of both linaclotide and its active metabolite are below the measurable limit following administration of the multiple doses by oral route. The therapy of lactating mothers is not expected to expose breastfed infants to linaclotide or MM-419447 metabolite.[23] 

No information is available regarding the effects of linaclotide and its metabolite on breast milk production. While prescribing the linaclotide to the lactating mother, advantages of breastfeeding on infant's overall health and development should be taken into consideration along with the maternal need of the linaclotide for the medical condition and any potential harmful effects on the infants on mother's milk from linaclotide or poorly managed underlying maternal disease.

Pediatrics

Due to the risk of serious dehydration, linaclotide use is not recommended in patients less than two years of age. In preclinical studies, because of age-dependent enhanced agonism of GC-C receptors in neonatal mice (equivalent human age is 0 to 28 days), linaclotide, after oral administration, induced elevated fluid secretion, which was associated with higher mortality rates within the first 24 hours from rapid and severe dehydration.

A GC-C ontogeny study was conducted in children of age six months to less than 18 years to measure levels of GC-C mRNA expression in samples of mucosal tissue of the duodenum and colon with the aim of assessing the risk of diarrhea and severe dehydration as a result of GC-C agonism in this population. According to the results, the age-dependent trend in the expression of intestinal GC-C does not exist in children aged 2 to below 18 years. However, sufficient data about intestinal CG-C expression are not available in children less than two years of age, and therefore, the risk of developing adverse event diarrhea and its potentially dangerous consequences are not evaluated.

Geriatrics

Clinical trials revealed that linaclotide is safe and effective in the geriatric group. The incidence of diarrhea might increase when linaclotide is taken alone or in combination with other medications that cause constipation.[24] In general, caution should exercise while selecting the dose of linaclotide for elderly patients reflecting a higher prevalence of reduced functions of vital organs (kidney, liver, and heart), coexisting medical conditions, and polypharmacy.

Administration

Dosage Forms and Strengths

Linaclotide is supplied as capsule dosage form and contains linaclotide-coated beads in a hard gelatin shell. In the market, linaclotide is available in various strengths such as 72 mcg, 145 mcg, and 290 mcg for oral administration. Inactive ingredients of the 72 mcg capsule are slightly different from the 145 mcg and 290 mcg capsules.

The inactive components of linaclotide 72 mcg capsules include L- histidine, calcium chloride dihydrate, microcrystalline cellulose, talc, and polyvinyl alcohol. The capsule shell is made of ingredients such as gelatin and titanium dioxide.

The inactive elements of linaclotide 145 and 290 mcg capsules include hypromellose, calcium chloride dihydrate, microcrystalline cellulose, and L-leucine. The capsule shell is made of the same ingredients, gelatin and titanium dioxide used for a 72 mcg capsule.

Recommended Dosages

• The recommended dosage of linaclotide for irritable bowel syndrome with constipation (IBS-C) is 290 mcg taken by mouth once daily.[25]
• The recommended dosage of linaclotide for chronic idiopathic constipation (CIC) is 145 mcg ingested by oral route once a day. Still, a smaller dosage of 72 mcg once a day may be prescribed according to individual presentation and tolerability.[16][26]

Preparation and Administration Instructions

• Linaclotide is taken orally on an empty stomach, a minimum of 30 minutes before breakfast or the first meal of the day.
• If a dosage is missed, skip the missed dosage, and take the next dosage at the regularly scheduled time. Do not take two dosages together at the same time.
• It is recommended not to open, crush or chew linaclotide capsule or contents, and instead, an intact capsule is swallowed.
• For adult patients with dysphagia or odynophagia, capsules of linaclotide can be opened and administered orally with either water or in applesauce or administered with water through a feeding tube, nasogastric, or gastrostomy tube. A sprinkling of linaclotide beads in other liquids or on other soft foods has not been scientifically tested.
• Linaclotide is stored at room temperature (25 C (77 F)), and excursions are allowed between 15 C and 30 C (59 F and 86 F). It is recommended to keep linaclotide in the original container. It should not be subdivided to store in a pillbox or repacked. The lid of the container needs to be closed tightly. Linaclotide needs protection from humidity, and therefore, its container is kept in a dry place along with the desiccant in it. The container is stored securely for safety purposes. 

Oral Administration in Water

• Take a clean cup containing about 30 mL of room-temperature bottled water.
• Then, open the capsule and empty the whole contents (beads) into the water.
• Dissolve off the medicine coated on the beads’ surface by gently swirling the beads and water for a minimum of 20 seconds. Beads are insoluble and will remain visible.
• The whole mixture of beads and water is consumed immediately.
• Pour an additional 30 mL (about 1 ounce) of water into any beads sticking around in the cup, swirl for at least 20 seconds, and swallow it immediately. It is not essential to consume all the beads to deliver the full dose. It is recommended not to store the bead-water mixture for later use.

Oral Administration in Applesauce

Take a clean container and add a teaspoonful of room-temperature applesauce into it. Then, open the intact capsule and disperse the entire medicine on applesauce. Swallow the bead-applesauce mixture immediately. Do not chew the beads. Storage of the mixture for later use is not advisable.

Administration with Water Via a Nasogastric or Gastrostomy Tube

• Open the linaclotide capsule and sprinkle the beads into a clean container with 30 mL of room-temperature bottled water.
• Mix the beads and water by gently swirling the beads for a minimum of 20 seconds.
• Draw up a mixture of the beads and water into a catheter-tipped syringe of appropriate size and dispense the contents of the syringe into the tube by applying rapid and steady pressure (10 mL/10 seconds).
• Another 30 mL of water can be added to any beads left in the container, and then the entire process is repeated.
• After administering the dose (bead-water mixture), flush the feeding tube, nasogastric or gastrostomy, with at least 10 mL of water. 

Note: It is not essential to flush all the beads through the feeding tube to deliver the complete dosage

On economic evaluation, linaclotide is a less expensive option with equal efficacy for treating adults with CIC and IBS-C compared with other drugs such as lubiprostone.[27]

Adverse Effects

Linaclotide is a well-tolerated secretagogue and promotility drug. Its side effects are secondary to its mechanism of action. The adverse effects are usually mild and confined to the gastrointestinal tract.[16]

The most common side effect is diarrhea.[14][15] During post-marketing surveillance, cases of severe diarrhea associated with dehydration have been reported. The dehydration presented with tachycardia, hypotension, dizziness, syncope, and electrolyte abnormalities (hypokalemia, hyponatremia), necessitating hospitalization and intravenous fluid therapy.

Diarrhea often starts during the first two weeks of initiating linaclotide therapy. The frequency of severe diarrhea is higher among the patients receiving larger dosages. If severe diarrhea occurs, suspend the dose, and rehydrate the patient.

Other most common side effects are abdominal pain, flatulence, abdominal distension, the urgency of defecation, fecal incontinence, viral gastroenteritis, and headache. Vomiting and Gastroesophageal reflux disease are less common unwanted effects.

Diarrhea and abdominal pain are the most common events which require dose suspension, decrease in the dosage, or discontinuation of the linaclotide treatment.

Gastrointestinal reactions (hematochezia, nausea, and rectal hemorrhage) and various hypersensitivity reactions (anaphylaxis, angioedema, and rash (including hives or urticaria)) have been reported during post-FDA approval use of linaclotide. Anaphylaxis is a life-threatening type-I allergic reaction mediated by IgE and affects multiple systems in the body. It is an emergency condition that requires immediate treatment with intramuscular epinephrine injection. Urticaria is also a type-I hypersensitivity reaction but involves only skin and subcutaneous tissue and is responsive to oral antihistamines such as chlorpheniramine maleate.

Overdosage

The safety profile in 22 healthy subjects who were orally administered the single linaclotide doses of 2897 mcg was consistent with that of the overall linaclotide treated population, along with diarrhea being the most frequently reported adverse event.

Nonclinical Toxicology (Carcinogenesis, Mutagenesis, Impairment of Fertility)

Carcinogenesis

In carcinogenicity studies performed over two years, linaclotide was not tumorigenic in mice at doses up to 6000 mcg/kg/day and in rats at doses up to 3500 mcg/kg/day. Based on 60-kg body weight, the maximum recommended dose for humans is approximately 5 mcg/kg/day. At the tested linaclotide dose levels in animals, only limited systemic exposure to parent drug or active metabolite was obtained, whereas no detectable exposure was attained in humans. Therefore, human and animal dosages cannot be directly compared for evaluating relative exposure.

Mutagenesis

Linaclotide was not genotoxic in the in vitro studies, including bacterial reverse mutation (Ames) assay and chromosomal aberration assay in cultured human lymphocytes of peripheral blood.

Impairment of Fertility

Linaclotide did not affect any reproductive function, including fertility in rats of both genders at oral dosages up to 100,000 mcg/kg/day.

Contraindications

Linaclotide use is not recommended in the following patients:

• Pediatric patients less than two years of age, as they are at risk of developing severe dehydration - in nonclinical studies, deaths due to diarrhea and severe dehydration were reported following orally administered linaclotide in neonatal mice
• Patients with known or suspected mechanical obstruction of the gastrointestinal tract.
• Patients who have experienced hypersensitivity reactions to linaclotide or any of the components of its formulation

Moreover, clinical trials have not been conducted to establish the safety and effectiveness of linaclotide in patients aged younger than 18 years.

Monitoring

The patients on linaclotide need follow-up to evaluate the response to therapy and manage adverse drug reactions if they develop. In addition, these patients can be monitored for fissures and hemorrhoids, complications of the underlying medical condition.[28]

Toxicity

Accidental ingestion of linaclotide in children, particularly under two years of age, may cause severe diarrhea and dehydration. Patients need counseling regarding the necessity for keeping the linaclotide container out of reach of children and discarding the unused linaclotide appropriately.[29]

Enhancing Healthcare Team Outcomes

Irritable bowel syndrome with prominent constipation (IBS-C) and chronic idiopathic constipation (CIC) are functional gastrointestinal disorders connected with constipation. IBS-C and CIC together affect about 20% of the general population, including the geriatric group, impairing the overall quality of life. When patients do not respond adequately to over-the-counter therapies, they need safe and effective long-term prescribed treatment. Patients might be intolerant to the more well-established medicines currently available in the market. For adults, linaclotide is a novel remedy with a favorable safety profile.[3] 

After obtaining the patient's informed verbal consent, providers such as primary care physicians, gastroenterologists, nurse practitioners, and physician assistants prescribe linaclotide and set realistic goals for treatment outcomes. Nurses administer the linaclotide via feeding tube in in-patient settings. At discharge, they have opportunities to counsel the patients regarding the drug dosage, administration, treatment compliance, and circumstances when medical attention is necessary.

During follow-up visits, nurses can detect and report adverse effects to the consultants. Pharmacists review the drug dosage, administration, and storage process at all kinds of healthcare settings and report the concerns to the physicians. The patients are advised to read the FDA-approved labeling and take medicine regularly, at least 30 minutes before the first meal of the day, and follow the prescriber's advice. A high fiber diet, adequate fluid intake, and exercise have added benefits while on linaclotide. Patients should keep the medicine out of reach of children and dispose of the unused supply. Families should contact the poison control center immediately in cases of accidental ingestion by children. The collaboration and open communication among interprofessional healthcare team members will positively impact patient outcomes.

Review Questions

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Disclosure: Urvashi Kalola declares no relevant financial relationships with ineligible companies.

Disclosure: Yuvraj Chowdhury declares no relevant financial relationships with ineligible companies.