Tolvat 15

Indications

• Autosomal dominant polycystic kidney disease (ADPKD) in adults
• Hyponatraemia secondary to the syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Dosage

Children: Refer to the BNF for Children for specific dosing information.

Adults: Initially, 15 mg once daily, which may be increased based on clinical response. The maximum recommended dose is typically 60 mg once daily.

Mechanism of action

Tolvaptan selectively and competitively antagonizes the arginine vasopressin receptor 2 (V2). By inhibiting V2 receptors in the renal collecting ducts, tolvaptan prevents the insertion of aquaporins into the luminal membranes, leading to decreased water reabsorption, increased urine volume, decreased urine osmolality, and an increase in serum sodium levels. This mechanism is particularly beneficial for patients with heart failure, where vasopressin levels are often elevated.

Pharmacodynamics

In a dose-dependent manner, tolvaptan increases urine volume and fluid intake, resulting in a negative fluid balance. Administration leads to significant increases in serum sodium and osmolality within 4-8 hours, effects that can persist for up to 24 hours. Increased doses correlate with greater changes in serum sodium and osmolality, while urine osmolality decreases and free water clearance increases shortly after administration.

Pharmacokinetics

Tolvaptan is absorbed orally, with peak plasma concentrations typically occurring within 1-2 hours post-administration. It undergoes hepatic metabolism primarily via CYP3A4, and its elimination half-life varies between 5 to 12 hours. The drug exhibits linear pharmacokinetics within the therapeutic range and is primarily eliminated through feces, with a minor portion excreted in urine.

Contra-indications

• Chronic nephritis
• Vascular disease
• Coronary artery disease

Adverse effects

• Hyponatraemia
• Thirst
• Polyuria
• Nausea
• Fatigue
• Dizziness
• Headache

Interactions

• Grapefruit juice (severe - increases exposure)
• St John's wort (severe - decreases exposure)
• Cenobamate (moderate - decreases exposure)
• Mitotane (moderate - decreases exposure)
• Ciprofloxacin (moderate - increases exposure)
• Rifampicin (moderate - decreases exposure)
• Dronedarone (unknown - increases exposure)
• Antifungals, azoles (unknown - increases exposure)
• Cobicistat (unknown - increases exposure)
• Crizotinib (unknown - increases exposure)

Precautions

• Monitor for signs of fluid overload
• Caution in patients with a history of epilepsy
• Use with caution in patients with asthma
• Careful titration required in patients with chronic kidney disease

Pregnancy

Oxytocic effect in third trimester; caution advised.

Breast-feeding

Not known to be harmful.

Storage

Store below 30°C. Protect from light.

Formulations

• Tolvaptan 15 mg oral tablets
• Tolvaptan 30 mg oral tablets
• Tolvaptan 60 mg oral tablets

Mechanism of action

Tolvaptan is a selective and competitive arginine vasopressin receptor 2 antagonist. 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, decrease urine osmolality, and increase electrolyte-free water clearance to reduce intravascular volume and an increase serum sodium levels. Tolvaptan is especially useful for heart failure patients as they have higher serum levels of vasopressin. Tolvaptan is a vasopressin antagonist that blocks the binding of arginine vasopressin (AVP) at the V2 receptors of the distal portions of the nephron. Animal pharmacology studies indicated that tolvaptan should increase excretion of water without increasing excretion of electrolytes (aquaresis) and thus offer a means of correcting serum sodium concentration by inducing excretion of water without loss of serum electrolytes. Tolvaptan is about 29 times more selective for V2 receptors than for V1a receptors with virtually no binding to V1b receptors. Tolvaptan is a selective vasopressin V2-receptor antagonist with an affinity for the V2-receptor that is 1.8 times that of native arginine vasopressin (AVP). Tolvaptan affinity for the V2-receptor is 29 times greater than for the V1a-receptor. When taken orally, 15 to 60 mg doses of tolvaptan antagonize the effect of vasopressin and cause an increase in urine water excretion that results in an increase in free water clearance (aquaresis), a decrease in urine osmolality, and a resulting increase in serum sodium concentrations. Urinary excretion of sodium and potassium and plasma potassium concentrations are not significantly changed. Tolvaptan metabolites have no or weak antagonist activity for human V2-receptors compared with tolvaptan. Plasma concentrations of native AVP may increase (avg. 2-9 pg/mL) with tolvaptan administration.

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.