What is the recommended dosage of Tolvaptan (Tolvaptan) in Autosomal Dominant Polycystic Kidney Disease (ADPKD)?

Tolvaptan Dosing in ADPKD

Start tolvaptan at 45 mg upon waking and 15 mg eight hours later, then titrate weekly to a target dose of 90 mg in the morning and 30 mg in the afternoon, continuing treatment until approaching kidney replacement therapy if well-tolerated. 1

Initial Dosing Protocol

• Starting dose: 45 mg upon waking, followed by 15 mg eight hours later 1
• Titration schedule: Increase after at least 1 week if tolerated 1
• Target dose: 90 mg in the morning and 30 mg in the afternoon 1

The KDIGO 2025 guidelines provide the most authoritative dosing framework, establishing a clear three-step titration approach that balances efficacy with tolerability 1. This represents the current standard of care based on evidence showing tolvaptan reduces eGFR decline by 1.3 ml/min per 1.73 m² per year 1.

Titration Steps

Week 1 and beyond:

• Initial: 45 mg AM + 15 mg PM (8 hours later) 1
• Intermediate: 60 mg AM + 30 mg PM 1
• Target: 90 mg AM + 30 mg PM 1

Each dose escalation should occur after at least one week at the current dose level 1. The split-dosing regimen with an 8-hour interval is critical to maintain therapeutic effect while managing aquaresis 1.

Duration of Treatment

• Continue tolvaptan until approaching kidney replacement therapy if well-tolerated 1
• Treatment can be continued in patients aged >55 years 1
• Treatment can be continued when eGFR falls below 25 ml/min/1.73 m² if well-tolerated 1

This represents a significant update from earlier practice, as research has shown that patients with more advanced CKD stages still demonstrate pharmacodynamic response to tolvaptan, particularly in fractional free-water clearance 2, 3.

Dose Adjustments and Holds

Downtitrate or hold tolvaptan in these situations: 1

• Concurrent CYP3A inhibitors: Strong inhibitors (reduce clearance >80%) include itraconazole, ketoconazole, clarithromycin, and protease inhibitors; moderate inhibitors (reduce clearance 50-80%) include fluconazole, erythromycin, diltiazem, verapamil, and grapefruit juice 1
• Intolerance or side effects: Particularly aquaresis-related symptoms 1
• Elevated liver enzymes: See monitoring section below 1

Implement a "sick-day plan": 1

• Skip doses during situations with limited water access 1
• Hold during increased fluid losses (vomiting, diarrhea) 1
• Avoid during activities in warm weather without adequate hydration 1
• Interrupt treatment in any situation causing volume depletion 1

Mandatory Monitoring Requirements

Liver function tests: 1

• Monthly for the first 18 months 1
• Every 3 months thereafter until drug discontinuation 1
• Obtain morning blood samples before the tolvaptan dose 1

Discontinuation criteria for hepatotoxicity: 1

• Permanently discontinue if ALT or AST increase to ≥3× upper limit of normal (ULN) 1
• Discontinue if ALT or AST >2× ULN with signs/symptoms of liver injury 1

Approximately 5% of ADPKD patients treated with tolvaptan develop transaminase elevations >3× ULN compared to 1% with placebo, with most occurring in the first 18 months 1. These elevations typically resolve within 1-4 months after cessation 1.

Serum sodium monitoring: 1

• Check serum sodium levels to assess adequacy of water intake 1
• Morning samples before tolvaptan dose provide insight into hydration status 1

Fluid Management Requirements

Water intake is essential for tolerability: 1

• Patients must drink enough water to replace urinary losses 1
• Counsel patients to drink liquids without sugar or fat 1
• Adopt low-sodium intake to reduce polyuria 1
• Target 2-3 liters per day of water intake 4

Low osmolar intake reduces the degree of polyuria, making the treatment more tolerable 1, 5. This is a critical counseling point that directly impacts adherence.

Special Population Considerations

Pediatric patients: 1

• Tolvaptan is not routinely recommended for children and young people with ADPKD 1
• Off-label use can be considered at clinician discretion in children at high risk of early progression based on large total kidney volume, rapid kidney growth, or concerning family history 1
• Substantial polyuria may affect sleep and daily activities, requiring additional counseling and support during adolescence 1

Advanced CKD (eGFR <25 ml/min/1.73 m²): 1

• Continue treatment if well-tolerated 1
• Patients with lower GFRs show greater fractional free-water clearance response per functioning nephron 2
• Absolute changes in urine volume and osmolality are smaller at lower GFRs, but therapeutic benefit persists 2, 3

Common Pitfalls to Avoid

• Inadequate fluid counseling: Failure to emphasize the need for adequate water replacement leads to dehydration and poor tolerability 1, 5
• Missing the sick-day plan: Patients must understand when to hold doses to prevent volume depletion 1
• Insufficient monitoring: The monthly LFT requirement for 18 months is mandatory and non-negotiable 1
• Ignoring drug interactions: CYP3A inhibitors significantly increase tolvaptan levels and require dose adjustment or avoidance 1
• Premature discontinuation: Treatment should continue until approaching kidney replacement therapy unless contraindicated 1