Half-Life of Tolvaptan
The half-life of tolvaptan is approximately 12 hours in most patients, but can range from 3 hours for lower doses to 12 hours for higher doses due to prolonged absorption at higher doses. 1
Pharmacokinetic Profile
- Tolvaptan has a dose-dependent half-life, with lower doses (15 mg) having a half-life of approximately 3 hours, while higher doses (120 mg and above) have a half-life of approximately 12 hours 1
- Following oral administration, peak plasma concentrations of tolvaptan are observed between 2 and 4 hours post-dose 1
- The absolute bioavailability of tolvaptan following an oral dose of 30 mg is 56% (range 42-80%) 1
- Tolvaptan is highly protein-bound (>98%) in the plasma 1
Factors Affecting Half-Life
- Age: The half-life extends to 11-13 hours in older patients compared to 3 hours in healthy younger individuals (age 20-45 years) 1
- Renal function: In patients with hyponatremia of any origin, the clearance of tolvaptan is reduced to about 2 mL/min/kg, which may affect elimination half-life 1
- Hepatic impairment: Moderate or severe hepatic impairment decreases the clearance and increases the volume of distribution of tolvaptan, though these changes are not considered clinically relevant 1
Metabolism and Elimination
- Tolvaptan is metabolized almost exclusively by CYP3A4 1
- Following oral administration, about 40% of tolvaptan is recovered in urine (<1% as unchanged tolvaptan) and 59% in feces (19% as unchanged tolvaptan) 1
- The apparent clearance is approximately 4 mL/min/kg and does not appear to change with increasing dose 1
Drug Interactions Affecting Half-Life
- Strong CYP3A inhibitors: Ketoconazole increases tolvaptan's Cmax by 3.5 times and AUC by 5.4 times 1
- Moderate CYP3A inhibitors: Fluconazole increases tolvaptan's Cmax by 80% and AUC by 200% 1
- Grapefruit juice: Co-administration increases tolvaptan's Cmax by 90% and AUC by 60% 1, 2
- CYP3A inducers: Rifampin decreases both tolvaptan Cmax and AUC by about 85% 1
Clinical Implications of Half-Life
- For patients with ADPKD, tolvaptan reaches steady-state levels within 3 days due to its half-life of approximately 12 hours 3
- When discontinuing tolvaptan before procedures or surgery, the half-life should be considered to ensure adequate clearance 4
- For patients with renal impairment, the onset and offset of tolvaptan's effect on serum sodium are slower, despite similar peak increases in serum sodium levels 1