What is tolvaptan (vasopressin V2 receptor antagonist)?

Tolvaptan: Selective Vasopressin V2-Receptor Antagonist

Tolvaptan is an oral, selective vasopressin V2-receptor antagonist that promotes aquaresis (solute-free water excretion) to correct hyponatremia in patients with hypervolemic or euvolemic conditions. 1

Mechanism of Action

• Tolvaptan has 1.8 times the affinity for the V2-receptor compared to native arginine vasopressin (AVP), and its affinity for the V2-receptor is 29 times greater than for the V1a-receptor 1
• The drug selectively blocks V2 receptors in the collecting duct of the kidney, inhibiting water reabsorption without affecting sodium or potassium excretion 2, 1
• This mechanism increases free water clearance (aquaresis), decreases urine osmolality, and raises serum sodium concentrations 1, 3
• Urinary excretion of sodium and potassium and plasma potassium concentrations remain largely unchanged 1

Pharmacokinetics and Pharmacodynamics

• The onset of aquaretic and sodium-increasing effects occurs within 2-4 hours post-dose, with peak effects observed between 4-8 hours 1
• A single 60 mg dose produces approximately a 6 mEq increase in serum sodium and about 9 mL/min increase in urine excretion rate at peak effect 1
• About 60% of the peak effect on serum sodium is sustained at 24 hours post-dose 1
• The absolute bioavailability following a 30 mg oral dose is 56% (range 42-80%), and it decreases with increasing doses 1
• Peak concentrations occur 2-4 hours after dosing, and co-administration with high-fat meals doubles peak concentrations but does not affect overall exposure 1
• Tolvaptan is highly protein-bound (>98%) to both albumin and α1-acid glycoprotein 1
• The drug is metabolized by the CYP3A4 system, which creates potential for drug interactions 4

Clinical Indications

Tolvaptan is FDA-approved for treating clinically significant hypervolemic or euvolemic hyponatremia (serum sodium <135 mmol/L) associated with: 3, 5

• Heart failure
• Cirrhosis with ascites
• Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Efficacy in Clinical Trials

• In the SALT-1 and SALT-2 trials, tolvaptan 15-60 mg once daily (titrated to response) for up to 30 days produced significantly greater improvements in serum sodium levels compared to placebo 3
• Mean changes in serum sodium from baseline to day 4 were 3.62 mmol/L with tolvaptan versus 0.25 mmol/L with placebo (P < 0.001) 5
• By day 30, the difference was 6.22 mmol/L versus 1.66 mmol/L (P < 0.001) 5
• Benefits were observed in both mild hyponatremia (<135 mmol/L) and marked hyponatremia (<130 mmol/L) 3
• In the EVEREST trials involving heart failure patients, tolvaptan was superior to placebo in increasing serum sodium levels from baseline to day 7 3

Dosing and Administration

• Initial dosing typically starts at 15 mg once daily and can be titrated up to 60 mg daily based on serum sodium response 6, 7
• Doses above 60 mg do not increase aquaresis or serum sodium further 1
• Treatment should be initiated in a hospital setting for close clinical monitoring to prevent overly rapid correction 6
• Tolvaptan may be administered with or without food 1

Safety Considerations and Monitoring

Critical Monitoring Requirements

• Serum sodium levels must be closely monitored to avoid increases exceeding 8-10 mmol/L per day to prevent osmotic demyelination syndrome 6
• Patients with severe hyponatremia (serum sodium <125 mEq/L) are at particularly high risk for osmotic demyelination syndrome 6
• Fluid restriction should be avoided during the first 24 hours of treatment to prevent overly rapid correction 7

Common Adverse Events

• The most frequently reported adverse events are thirst (7.7%-40.3%), dry mouth (4.2%-23.0%), and polyuria (0.6%-31.7%), all consistent with the drug's mechanism of action 3, 5
• These pharmacodynamic effects result from increased free water excretion 3

Special Population Considerations

• In patients with congestive heart failure, oral clearance (CL/F) is reduced to 58.2% for NYHA Class 1-2 and 45.5% for NYHA Class 3-4 compared to healthy subjects 8
• In hepatic cirrhosis, CL/F is reduced to 58.0% relative to healthy subjects 8
• Patients with severe hepatic cirrhosis (Child-Pugh score ≥10) have a 64.8% larger central volume of distribution 8
• Liver toxicity concerns exist primarily with long-term use, particularly in polycystic kidney disease patients 6
• In cirrhotic patients, tolvaptan carries a higher risk of gastrointestinal bleeding (10% versus 2% with placebo) 9

Contraindications

Tolvaptan should not be used in: 7

• Patients who cannot sense or respond to thirst
• Anuric patients
• Hypovolemic patients
• Patients requiring urgent intervention to raise serum sodium acutely

Clinical Context and Limitations

• While tolvaptan effectively corrects hyponatremia, it has not been associated with significant improvements in mortality in heart failure patients compared to placebo 5
• Prolonged use leads to increased endogenous AVP levels, which theoretically could over-stimulate V1A receptors, potentially causing increased afterload and cardiac myocyte fibrosis 4
• However, after 52 weeks of therapy, no worsening of left ventricular dilatation was observed 4
• Physicians must be aware of potential drug interactions due to CYP3A4 metabolism 4