Tolvaptan

Tolvaptan is a selective vasopressin V2-receptor antagonist

Tolvaptan is used in the Treatment of Autosomal dominant polycystic kidney disease, Hyponatremia (chronic), euvolemic or hypervolemic.

Tolvaptan is absorbed from the gastrointestinal tract with a bioavailability of approx 40%. The Volume of distribution was approx 3 L with plasma protein binding: >99%, mainly to albumin. Tolvaptan is metabolized in the liver by the CYP3A4 enzyme and get very little renal elimination (<1% is excreted unchanged in the urine).

The Duration of Action of Tolvaptan was about 4 hours.

The Tmax of Tolvaptan was 2-4 hours, and Cmax was about 400 ng/ mL

The common side effects are thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria, and hyperglycemia.

Tolvaptan is available in dosage forms, such as tablets.

Tolvaptan is available in Europe, Japan, Australia, the USA, and India.

Tolvaptan is a selective and competitive arginine vasopressin receptor two antagonists. Vasopressin acts on the V2 receptors found in the walls of the vasculature and luminal membranes of renal collecting ducts. By blocking V2 receptors in the renal collecting ducts, aquaporins do not insert themselves into the walls, thus preventing water absorption. This action ultimately results in an increase in urine volume, decreased urine osmolality, and increased electrolyte-free water clearance to reduce intravascular Volume and increase serum sodium levels. Tolvaptan is especially useful for heart failure patients as they have higher serum levels of vasopressin.

Tolvaptan is available in the form of dosage forms, such as tablets.

Tolvaptan tablets were taken orally with or without food.

Tolvaptan is used in the Treatment of symptomatic and resistant to fluid restriction euvolemic or hypervolemic Hyponatremia associated with congestive heart failure, SIADH, and cirrhosis.

Tolvaptan is a selective vasopressin V2-receptor antagonist to slow kidney function decline in patients at risk for rapidly progressing autosomal dominant polycystic kidney disease (ADPKD). Also used to treat hypervolemic and euvolemic hyponatremia.

Tolvaptan is approved for its use in the following clinical indications:

● Autosomal dominant polycystic kidney disease: : Slow the progression of kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD)

● Hyponatremia (chronic), euvolemic or hypervolemic: Treatment of clinically significant hypervolemic or euvolemic Hyponatremia (serum sodium <125 mEq/L or less marked Hyponatremia that is symptomatic and resistant to fluid restriction), including patients with heart failure and syndrome of inappropriate antidiuretic hormone (SIADH).

● Limitations of use: Not indicated for use when urgent Treatment of Hyponatremia is required to prevent or treat serious neurological symptoms

Tolvaptan is available in various dosage strengths:15mg,30mg, 45mg, 60mg, 90mg

Tolvaptan is available in the form of a dosage form, such as tablets

• Dose Adjustment in Kidney Patients:

ADPKD : Use is contraindicated in patients who are anuric. Clinical studies included patients with eGFR as low as 25 mL/minute/1.73 m2.

Hypervolemic or euvolemic hyponatremia:

• CrCl ≥10 mL/minute: No dosage adjustment necessary.
• CrCl <10 mL/minute: Use not recommended (has not been studied and effects of tolvaptan on serum sodium levels is likely lost at very low levels of renal function); contraindicated in anuria.
• Dose Adjustment in Hepatic Impairment Patient

ADPKD: Use is contraindicated in patients with significant hepatic impairment or disease (or a history of). Monitor closely for hepatoxicity developing during use.

ALT, AST, or bilirubin increase to >2 times ULN or signs/symptoms of hepatotoxicity develop during use: Discontinue immediately, obtain repeat tests promptly within 48 to 72 hours, and continue testing as necessary; if laboratory abnormalities stabilize or resolve, Treatment may be reinitiated with increased monitoring as long as ALT and AST <3 times ULN.

● ALT or AST >3 times ULN: Do not use or reinitiate therapy.

● ALT or AST increased or signs/symptoms of hepatoxicity: Interrupt therapy, promptly evaluate hepatic function within 48 to 72 hours, and continue testing as necessary; if laboratory abnormalities stabilize or resolve, Treatment may be reinitiated with increased monitoring.

ALT or AST >3 times ULN: Permanently discontinue therapy if ALT or AST is >3 times ULN and any of the following occur: persistent symptoms of hepatic injury; total bilirubin >2 times ULN; INR >1.5; ALT or AST >5 times ULN for >2 weeks; ALT or AST >8 times ULN at any time.

Hypervolemic or euvolemic hyponatremia: Avoid use in patients with underlying liver disease, including cirrhosis; monitor closely for hepatotoxicity developing during use; discontinue use if signs/symptoms of hepatotoxicity develop (do not use for more than 30 days due to this potential risk).

• Dose Adjustment in Pediatric Patients.

Safety and efficacy not established

Tolvaptan is used in the Treatment of Autosomal dominant polycystic kidney disease, Hyponatremia (chronic), euvolemic or hypervolemic.

Grapefruit juice may increase tolvaptan serum concentrations. Management: Avoid concurrent use with grapefruit juice.

Tolvaptan may be contraindicated in the following.

• Itraconazole

itraconazole will increase the level or effect of tolvaptan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Larger doses of strong CYP3A4 inhibitors may produce larger increases in tolvaptan exposure. Concomitant use of tolvaptan with strong CYP3A4 inhibitors is contraindicated.

• Ritonavir

nirmatrelvir/ritonavir will increase the level or effect of tolvaptan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions. May increase risk of dehydration, hypovolemia, and hyperkalemia associated with tolvaptan.

Concerns related to adverse effects:

● Fluid retention/peripheral edema:

Development of peripheral edema due to treatment and/or disease state (pulmonary arterial hypertension) may occur. There have also been postmarketing reports of fluid retention requiring Treatment (eg, diuretics, fluid management, hospitalization) for heart failure. If clinically significant fluid retention develops (with or without weight gain), further evaluation is necessary to determine the cause and appropriate Treatment or discontinuation of therapy. Use with caution in patients with underlying heart failure due to potential complications from fluid retention. In a scientific statement from the American Heart Association, Tolvaptan has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: major) (AHA).

● Hematologic effects:

Dose-related decreases in hematocrit/hemoglobin may be observed, usually within the first few weeks of therapy with subsequent stabilization of levels by 4 to 12 weeks of Treatment. Monitor hemoglobin prior to treatment initiation, after 1 and 3 months, and every 3 months thereafter. Significant decreases in hemoglobin require further evaluation to determine the cause and specific management.

● Hepatotoxicity:

Tolvaptan is associated with transaminase elevations (ALT or AST ≥3 times ULN), and in a small number of cases may occur with elevations in bilirubin. Monitor transaminases at baseline and then monthly thereafter. Adjust dosage if elevations in liver enzymes occur without symptoms of hepatic injury or elevated bilirubin. In the postmarketing surveillance (with close monitoring), there have been rare cases of unexplained hepatic cirrhosis after prolonged therapy (>12 months) in patients with multiple comorbidities and drug therapies. There have also been cases of hepatic failure. Treatment should be stopped in patients who develop elevated transaminases either in combination with symptoms of hepatic injury (unusual fatigue, jaundice, nausea, vomiting, abdominal pain, and/or fever) or elevated bilirubin (≥2 times ULN); safety of reintroduction is unknown. Avoid use in patients with baseline serum transaminases >3 times ULN at baseline (monitoring for hepatotoxicity may be more difficult) or moderate to severe hepatic impairment. The combination of hepatocellular injury (transaminase elevations >3 times ULN) and bilirubin increased ≥2 times ULN are a marker for potential serious hepatotoxicity. Transaminase elevations are dose dependent, generally asymptomatic, occur both early and late in therapy, progress slowly, and are usually reversible after treatment interruption or discontinuation. Transaminase elevations may also spontaneously reverse while continuing Tolvaptan treatment. Consider the benefits of Treatment versus the risk of hepatotoxicity when initiating therapy in patients with WHO Class II symptoms.

● Hypersensitivity: Hypersensitivity reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), anaphylaxis, rash and angioedema have been observed.

● Pulmonary veno-occlusive disease: If signs of pulmonary edema occur, consider the possibility of pulmonary venous-occlusive disease; may require discontinuation of Tolvaptan.

Pregnancy Category X.

Risk Summary

Tolvaptan may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy.

The adverse reactions related to molecule Tolvaptan can be categorized as

• Common Adverse effects: Fluid retention, peripheral edema, decreased hematocrit/Hb (dose-related), elevated transaminase (ALT or AST ≥3 times ULN), hypersensitivity reactions (e.g. anaphylaxis, angioedema, rash, drug reaction with eosinophilia and systemic symptoms)
• Less Common adverse effects: Autoimmune hepatitis (e.g. exacerbation of underlying autoimmune hepatitis, hepatic injury, hepatic enzyme elevations), reduced Hb and hematocrit, fluid retention, peripheral edema, acute pulmonary edema, decreased sperm count.
• Rare Adverse effects: Unexplained liver cirrhosis in patients with multiple comorbidities and drug therapies (prolonged use); liver failure.

The clinically relevant drug interactions of Tolvaptan are briefly summarized here.

May increase plasma concentration with CYP2C9 inhibitors (e.g. fluconazole, amiodarone), CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir, erythromycin, diltiazem), tacrolimus and sirolimus. May decrease plasma concentration of hormonal contraceptives, warfarin, simvastatin, tadalafil and sildenafil. Decreased plasma concentration with rifampicin.

Potentially Fatal: Increased plasma concentration with ciclosporin. Enhanced hepatotoxic effect with glibenclamide.

Symptoms: Nausea, vomiting, dizziness, headache, sweating, blurred vision, hypotension.

Management: Supportive Treatment (e.g. blood pressure support).

Pharmacodynamics:

Urine volume and fluid intake increase in a dose dependent manner which results in overall negative fluid balance in patients taking tolvaptan. Increases in serum sodium and osmolality can be observed 4-8 hours post-administration and is maintained for 24 hours. The magnitude of serum sodium and osmolality change increases with escalating doses. Furthermore, a decrease in urine osmolality and increase in free water clearance can be observed 4 hours after post-administration of tolvaptan. The affinity for V2 receptors is 29x greater than that of V1a receptors and does not have any appreciable affinity for V2 receptors.

Pharmacokinetics:

• Absorption:  Absorbed from the gastrointestinal tract. Bioavailability: Approx. 40%. Time to peak plasma concentration: 2-4 hours.
• Distribution:  Volume of distribution: Approx. 3L/kg. Plasma protein binding: >99%, mainly to albumin.
• Metabolism:  Metabolized in the liver by CYP3A4.
• Excretion: Fecal- very little renal elimination (<1% is excreted unchanged in the urine).
• Elimination half-life: Approx. 12 hours.

1. https://pubmed.ncbi.nlm.nih.gov/28166521/
2. https://reference.medscape.com/drug/samsca-jynarque-tolvaptan-999103#3
3. https://go.drugbank.com/drugs/DB06212
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2643096/
5. https://journals.sagepub.com/doi/10.1177/0300060519882221
6. https://eje.bioscientifica.com/view/journals/eje/164/5/725.xml