Tenapanor

Introduction Overview

Generic Name

tenapanor

Brand Name

Ibsrela

Dosage Form

Tablets

Drug Class

NHE3 inhibitors

Pharmacokinetics

Absorption:
Tenapanor, marketed as Ibsrela, exhibits minimal systemic absorption following oral administration due to its targeted mechanism acting primarily within the gastrointestinal tract. Its localized activity in the intestinal epithelium strongly correlates with its pharmacodynamic action rather than systemic drug levels. Clinical pharmacokinetic studies have demonstrated that tenapanor plasma concentrations are generally low or undetectable, indicating limited translocation across the intestinal barrier. This pharmacokinetic property minimizes systemic side effects and supports its safety profile for chronic use in IBS-C patients.

Distribution:
Given the limited absorption, tenapanor's systemic distribution is minimal. The drug acts locally on the luminal surface of the small intestine and colon where sodium-hydrogen exchanger 3 (NHE3) proteins are expressed. The distribution within the gut mucosa allows for effective inhibition of sodium absorption without significant systemic exposure. No significant data indicate tenapanor distributes to extraintestinal tissues, which correlates with the low incidence of systemic adverse events.

Metabolism:
Tenapanor undergoes negligible systemic metabolism because it remains largely within the gastrointestinal tract. The drug is not significantly metabolized by hepatic enzymes or intestinal flora in a way that produces active metabolites. This lack of systemic metabolism contributes to its predictable pharmacological effects and reduces the risk of metabolic drug interactions. Stability assays confirm that tenapanor retains its chemical integrity within the intestinal lumen.

Elimination:
The primary route of elimination is fecal, as tenapanor is excreted largely unchanged in the stool. Renal elimination is minimal to none due to poor systemic absorption. This excretion mode supports its targeted therapeutic effects by maintaining drug presence within the intestinal lumen for adequate durations. The elimination half-life has limited clinical relevance due to non-systemic disposition, though dosing every 12 hours provides steady pharmacodynamic effect.

Overall, tenapanor’s pharmacokinetic profile supports its function as a locally acting agent in the gastrointestinal tract with negligible systemic absorption, metabolism, and renal elimination, which underpins its efficacy and safety in treating IBS-C.

Dosage Forms

Available Dosage Forms:
Ibsrela is available as oral tablets formulated for twice-daily administration. The tablets are intended to be taken whole and are designed to optimize local gastrointestinal delivery and effect. Currently, the marketed formulation is a film-coated tablet intended for oral use.

Dosages for Adults and Adolescents:
The standard adult dosing regimen for Ibsrela in the treatment of irritable bowel syndrome with constipation (IBS-C) is one tablet taken orally two times daily, administered immediately before breakfast (or the first meal of the day) and immediately before dinner. This dosing schedule aids in maximizing the drug's local gastrointestinal effect on sodium absorption during periods of intake. The safety and efficacy in pediatric patients less than 18 years old have not been established, and use in this population is not recommended.

Specific Patient Populations:
Use in children younger than 6 years old is contraindicated due to the risk of severe diarrhea and dehydration. Patients aged 6 to less than 18 years are also advised against using Ibsrela because of potential harm. There is limited data on use during pregnancy and lactation; thus, treatment is recommended only if the potential benefits justify the potential risks. Dose adjustments in renal or hepatic impairment are not necessary given minimal systemic absorption, though clinical judgment is advised. No specific modifications are indicated based on age or sex in adult patients.

The current marketed Ibsrela tablet contains tenapanor hydrochloride as the active ingredient with inactive ingredients including colloidal silicon dioxide, hypromellose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, propyl gallate, stearic acid, tartaric acid, titanium dioxide, and triacetin to enhance stability and bioavailability within the gastrointestinal tract.

Mechanism Of Action

Tenapanor, the active moiety in Ibsrela, functions as a selective inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3), an integral membrane protein expressed predominantly on the luminal surface of the epithelial cells lining the small intestine and colon. NHE3 mediates the absorption of sodium ions from the intestinal lumen into enterocytes, coupled with proton extrusion. By inhibiting NHE3, tenapanor effectively decreases sodium uptake in the gastrointestinal tract, resulting in increased luminal sodium concentration.

This elevated luminal sodium concentration leads to osmotic retention of water within the intestinal lumen, which softens stool consistency and increases stool water content, thereby accelerating intestinal transit time. Such action relieves constipation symptoms associated with irritable bowel syndrome with constipation (IBS-C). The reduction of sodium absorption also reduces intestinal fluid absorption, contributing to softer stools and more frequent bowel movements.

Beyond its effect on sodium absorption and stool consistency, tenapanor's inhibition of NHE3 decreases intestinal phosphate absorption as a secondary effect, which has implications for other indications such as hyperphosphatemia in chronic kidney disease. However, its primary approved use is for IBS-C.

Comparatively, Ibsrela's mechanism is distinct from other IBS-C treatments such as linaclotide or lubiprostone, which act through guanylate cyclase-C receptor activation or chloride channel modulation, respectively. Tenapanor's unique approach targeting sodium transport provides an alternative pathway for managing IBS-C symptoms.

Clinical studies have demonstrated that tenapanor’s local inhibition of NHE3 leads to significant improvements in constipation and abdominal pain associated with IBS-C, linking molecular action directly to symptom relief. Its minimal systemic absorption enhances its safety profile by limiting systemic side effects.

Pharmacological Actions

Selective inhibition of sodium/hydrogen exchanger isoform 3 (NHE3) on intestinal epithelial cells.
Reduction of sodium absorption in the gastrointestinal tract, increasing luminal sodium concentration.
Promotion of osmotic retention of water in the intestinal lumen, softening stool consistency.
Acceleration of intestinal transit time by increasing stool water content.
Secondary decrease in intestinal phosphate absorption due to NHE3 inhibition.
Minimal systemic exposure reducing risk of systemic adverse effects.
Improvement of bowel movement frequency and stool form in IBS-C patients.
Reduction of abdominal pain and discomfort associated with irritable bowel syndrome.
Potential modulation of gut electrolyte balance impacting motility and secretion.
Distinct pathway compared to other IBS-C drugs, providing therapeutic alternatives.
Localized action within the gastrointestinal tract with negligible systemic metabolism.
No significant interaction with hepatic cytochrome P450 enzymes, reducing drug interactions.
Preservation of enterocyte integrity while modulating ion transport.
Facilitation of improved quality of life in IBS-C through symptom control.

Therapeutic Or Clinical Uses

Treatment of irritable bowel syndrome with constipation (IBS-C) in adults.
Alleviation of constipation symptoms such as infrequent stools and hard stool consistency.
Reduction of abdominal pain and discomfort associated with IBS-C.
Management of bowel movement regularity in IBS-C patients.
Alternative treatment for patients intolerant or unresponsive to other IBS-C therapies.
Potential off-label use in disorders characterized by impaired intestinal sodium transport (pending clinical evidence).
Improvement of patient quality of life by relieving symptoms of IBS-C.
Use in patients seeking non-systemic gastrointestinal therapies.
Adjunct therapy in therapeutic regimens focused on gut motility and secretion.
Demonstrated safety and efficacy in multiple clinical trials leading to FDA approval.
Non-habit forming agent for chronic management of IBS-C.
Potential use in adult patients with contraindications to other laxatives or secretagogues.
Treatment indicated only for patients age 18 years and older due to safety concerns.
Not established for use in pediatric populations or during pregnancy.
No indication for use in patients with known bowel obstruction or intestinal blockage.

Side Or Adverse Effects

Diarrhea, which can be severe and may necessitate discontinuation of therapy.
Abdominal distension characterized by swelling or a sensation of fullness and pressure.
Flatulence (excessive gas formation in the gastrointestinal tract).
Dizziness reported in some patients during treatment.
Potential dehydration in cases of severe diarrhea due to fluid and electrolyte loss.
Gastrointestinal discomfort including cramps or abdominal pain.
Possible electrolyte imbalances secondary to altered sodium absorption.
No reported significant systemic adverse effects due to low systemic absorption.
Allergic reactions are rare but possible, including rash or hypersensitivity symptoms.
May exacerbate symptoms in patients with pre-existing bowel obstruction.
Potential for worsened dehydration risk in pediatric patients, contraindicating use in children under 6.
Mild to moderate adverse events typically resolve upon dose adjustment or discontinuation.
Low incidence of dizziness suggests possible effects on volume status or electrolyte changes.
Monitor for signs of severe diarrhea or dehydration during therapy initiation or dose escalation.
No evidence of hepatotoxicity or nephrotoxicity from available clinical data.

Precautions

Do not administer to children younger than 6 years due to risk of severe diarrhea and dehydration.
Use with caution in pediatric patients aged 6 to less than 18 years; not recommended due to safety concerns.
Avoid use in patients with known or suspected bowel obstruction or intestinal blockage.
Monitor for diarrhea severity and signs of dehydration during treatment.
Exercise caution in patients with underlying electrolyte imbalance or risk factors for dehydration.
Inform healthcare providers of all concomitant medications to assess potential interactions.
Pregnant or breastfeeding women should use only if benefits outweigh risks; data insufficient.
Patients should adhere strictly to dosing before meals to optimize efficacy.
Do not exceed recommended dose or combine doses to compensate for missed administration.
Store tablets properly in original container with desiccant to maintain stability.
Patients should stay adequately hydrated during treatment.
Avoid repackaging tablets to prevent moisture degradation.
Educate patients regarding potential gastrointestinal side effects and when to seek medical attention.
Assess renal function prior to initiation although dose adjustment is usually unnecessary.
Regular clinical monitoring advised to evaluate therapeutic response and adverse effects.

Warnings

Severe diarrhea is the most significant adverse effect and may lead to dehydration.
Should not be given to children less than 6 years due to risk of severe gastrointestinal adverse events.
Not recommended for patients aged 6 to less than 18 years as it may cause harm.
Stop drug and seek medical advice promptly if severe diarrhea develops.
Avoid use in patients with bowel obstruction as it may worsen the condition.
Risk of electrolyte shifts and dehydration requires monitoring, especially in vulnerable populations.
Use during pregnancy only if clearly needed; potential fetal risk unknown.
Keep out of reach of children to prevent accidental ingestion and possible severe side effects.
Concomitant use with other laxatives may increase risk of diarrhea and related complications.
Discontinue if severe abdominal discomfort or symptoms of obstruction arise.
Monitor for signs of volume depletion particularly in elderly or debilitated patients.
Patients should be informed about the signs of dehydration and advised on fluid intake.
No evidence for carcinogenicity, mutagenicity, or fertility impairment, but long-term safety continues to be monitored.
Patients with inflammatory bowel diseases were not included in clinical trials; safety unknown.
Inadequate safety data in patients with severe hepatic or renal impairment; caution is warranted.

Contraindication

Known hypersensitivity to tenapanor or any inactive ingredient in Ibsrela.
Patients diagnosed with or suspected to have bowel obstruction or intestinal blockage.
Children less than 6 years of age due to severe safety concerns.
Concomitant use with other medications that may exacerbate diarrhea without medical supervision.
Patients with a history of severe dehydration or fluid-electrolyte imbalance who cannot maintain hydration.
Patients with severe renal or hepatic impairment where safety is not established.
Use contraindicated in patients with known gastrointestinal conditions predisposed to obstruction.
Patients who cannot reliably follow dosing instructions or fluid intake recommendations.
Combination with other drugs causing significant gastrointestinal motility changes without clinician oversight.
Patients with intestinal malabsorption syndromes interfering with drug activity or safety.
Contraindicated during any acute abdominal conditions requiring surgical intervention.
Patients with known sensitivity to NHE3 inhibitors or similar pharmacological agents.
Avoid use in patients with unstable cardiovascular conditions predisposing to adverse events from dehydration.
Patients lacking access to prompt medical care for management of severe diarrhea or dehydration.
Use contraindicated if known hypersensitivity reactions such as Stevens-Johnson syndrome have occurred.

Drug Interactions

Limited systemic absorption reduces potential for cytochrome P450 mediated interactions.
Concomitant use with other laxatives or osmotic agents may increase risk or severity of diarrhea.
Caution with medications affecting electrolyte balance (e.g., diuretics, corticosteroids) as combined effects may cause hypovolemia or electrolyte disturbances.
No significant interactions reported with common medications including antihypertensives or antidiabetics.
Potential pharmacodynamic interaction with other drugs altering gastrointestinal motility.
Use caution when combined with drugs that have narrow therapeutic indices affected by fluid and electrolyte changes.
No known interactions with proton pump inhibitors or H2 blockers based on current data.
No reports of altered drug absorption or bioavailability of concomitant oral medications.
Monitoring advised when initiating or discontinuing Ibsrela concomitantly with other gastrointestinal agents.
Interactions with herbal supplements have not been extensively studied; caution recommended.
No known interaction affecting anticoagulants or antiplatelet agents.
No evidence of increased risk of interaction with over-the-counter vitamins or minerals.
No effect on cytochrome P450 enzymes minimizing risk of enzyme induction or inhibition.
Concurrent use with medications causing dizziness or hypotension may necessitate monitoring due to diarrhea-induced volume changes.
Potential additive adverse gastrointestinal effects when combined with irritant drugs.

Preparations Of The Drug

Ibsrela is formulated as film-coated oral tablets containing tenapanor hydrochloride.
Inactive ingredients include colloidal silicon dioxide, hypromellose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, propyl gallate, stearic acid, tartaric acid, titanium dioxide, and triacetin.
Tablets are designed to be taken by mouth twice daily before meals for optimal efficacy.
Packaging includes moisture-protective desiccant to maintain tablet stability.
Available in containers that protect from humidity with tight-sealing caps.
Storage recommended at controlled room temperature between 68°F and 77°F (20°C and 25°C).
Tablets should not be repackaged or removed from original container to avoid moisture degradation.
Prescribed dosages require strict adherence to timing relative to meals.
No available formulations for pediatric use or parenteral administration.
Manufactured by Ardelyx, Inc., adhering to regulatory standards for clinical quality and safety.
Supply chain incorporates quality control to ensure consistent drug content and release profiles.
No current generic formulations; marketed exclusively under brand name Ibsrela.
Developed specifically for targeted inhibition of NHE3 in the gastrointestinal tract.
In clinical use since FDA approval date, September 12, 2019.
Patient counseling includes instructions on storage conditions and handling to maintain medication integrity.