How does Tolvaptan (vasopressin receptor antagonist) work and what is its recommended dose for treating hyponatremia?

Mechanism of Action and Dosing of Tolvaptan

How Tolvaptan Works

Tolvaptan is a selective vasopressin V2-receptor antagonist that blocks the action of antidiuretic hormone (ADH) in the kidney's collecting ducts, causing increased excretion of free water without significant loss of sodium or potassium (aquaresis), thereby raising serum sodium levels. 1

Pharmacological Mechanism

• Tolvaptan has an affinity for the V2-receptor that is 1.8 times that of native arginine vasopressin (AVP), and its affinity for the V2-receptor is 29 times greater than for the V1a-receptor 1
• When administered orally at doses of 15-60 mg, tolvaptan antagonizes vasopressin effects and increases urine water excretion, resulting in increased free water clearance, decreased urine osmolality, and increased serum sodium concentrations 1
• Urinary excretion of sodium and potassium and plasma potassium concentrations are not significantly changed, distinguishing it from traditional diuretics 1
• The onset of aquaretic and sodium-increasing effects occurs within 2-4 hours post-dose 1
• Peak effect of approximately 6 mEq increase in serum sodium occurs between 4-8 hours post-dose, with about 60% of the peak effect sustained at 24 hours 1

Clinical Pharmacodynamics

• Tolvaptan is metabolized almost exclusively by CYP3A enzymes 1
• The drug has high protein binding (>98%) to albumin and α1-acid glycoprotein 1
• Following oral administration, peak concentrations are observed between 2-4 hours post-dose 1
• The half-life ranges from approximately 3 hours for a 15 mg dose to approximately 12 hours for 120 mg and higher doses 1

Recommended Dosing

The recommended starting dose is 15 mg once daily upon waking, with dose titration at intervals of at least 24 hours to 30 mg once daily, and then to a maximum of 60 mg once daily as needed to raise serum sodium. 1, 2

Dosing Protocol

• Tolvaptan must be initiated and re-initiated only in a hospital setting where serum sodium can be monitored closely 1
• Treatment should always be started in the hospital with close clinical monitoring and assessment of serum sodium levels 2
• After 24 hours, the dose may be increased to 30 mg once daily, then to 60 mg once daily until either maximum dose or normonatremia is reached 2
• Doses above 60 mg do not increase aquaresis or serum sodium further 1

Monitoring Requirements

• Serum sodium levels should be closely monitored to avoid increases of more than 8-10 mmol/L per day 2
• Morning blood samples should be obtained before the tolvaptan dose is taken 2
• Too rapid correction of hyponatremia (>12 mEq/L/24 hours) can cause osmotic demyelination syndrome resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, and death 1
• In susceptible patients, including those with severe malnutrition, alcoholism, or advanced liver disease, slower rates of correction may be advisable 1

Duration of Treatment

• The FDA recommends limiting treatment duration to 30 days due to risk of liver injury 1
• However, long-term safety and efficacy has been demonstrated in some studies with treatment extending beyond 2 years 2
• In the SALTWATER study, 111 patients received oral tolvaptan for a mean follow-up of 701 days, providing 77,369 patient-days of exposure 3

Special Population Considerations

• For patients with uncompensated liver cirrhosis, 50% of the standard dose is recommended as metabolism is approximately 60% slower 2
• In China and Japan, lower doses of tolvaptan (7.5-15 mg/day) have been approved to control ascites 2
• In patients with hyponatremia of any origin, the clearance of tolvaptan is reduced to about 2 mL/min/kg 1

Clinical Efficacy

• In the SALT-1 and SALT-2 trials, patients receiving tolvaptan 15-60 mg once daily (titrated according to response) for up to 30 days experienced significantly greater improvements in serum sodium levels compared to placebo 4, 5
• Significant improvement in serum sodium concentration is typically observed by the fourth day of treatment 2
• Effects are maintained until treatment discontinuation, with sodium levels gradually dropping to baseline after stopping treatment 2
• In cirrhotic patients with hyponatremia, tolvaptan was effective in raising serum sodium, with average daily area under the curve for serum sodium significantly greater from baseline to day 4 and day 30 6

Common Side Effects

• The most frequently reported adverse events are thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria, and hyperglycemia 1
• These side effects result from the pharmacodynamic effects of the drug 4
• In the SALTWATER study, the most common adverse effects attributed to tolvaptan were pollakiuria, thirst, fatigue, dry mouth, polydipsia, and polyuria 3

Important Contraindications

• Tolvaptan is contraindicated in patients with anuria, hypovolemic hyponatremia, patients unable to respond appropriately to thirst, and with concomitant use of strong CYP3A inhibitors 1
• Tolvaptan should not be used for autosomal dominant polycystic kidney disease (ADPKD) outside of the FDA-approved REMS due to risk of hepatotoxicity 1
• Avoid concomitant use with moderate CYP3A inhibitors and strong CYP3A inducers 1

Drug Interactions

• Strong CYP3A inhibitors such as antifungals, antibiotics, and protease inhibitors should be avoided, as well as grapefruit juice 2
• Monitor serum potassium in patients with potassium >5 mEq/L or on drugs known to increase potassium (angiotensin receptor blockers, ACE inhibitors, potassium-sparing diuretics) 1