From the Guidelines
Hypoalbuminemia increases free valproate levels.
Mechanism
- The binding of valproate to albumin determines the free fraction, which is the biologically active fraction that diffuses across biological membranes to tissues.
- When plasma protein amount decreases, the capacity of valproate to bind to protein decreases and valproate-free fraction increases, similar to beta-lactam antibiotics 1.
Clinical Implications
- In patients with hypoalbuminemia, the free fraction of valproate may be increased, potentially leading to increased pharmacological effects or toxicity.
- This is particularly relevant in critically ill patients, where hypoalbuminemia is common and valproate is often used for seizure control or other indications.
- Therapeutic drug monitoring (TDM) of valproate may be necessary in patients with hypoalbuminemia to ensure optimal dosing and minimize the risk of adverse effects 1.
From the FDA Drug Label
Protein Binding: The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 μg/mL to 18.5% at 130 μg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin).
Hypoalbuminemia is not explicitly mentioned, but it can be inferred that conditions that affect protein binding, such as hypoalbuminemia, may increase free valproate levels.
- Hypoalbuminemia may increase free valproate levels due to reduced protein binding of valproate. 2
From the Research
Factors Affecting Free Valproate Levels
- Hypoalbuminemia is a significant factor that increases free valproate levels in patients, as valproic acid is highly protein-bound and its free fraction increases with decreasing serum albumin levels 3, 4, 5.
- The free fraction of valproic acid can increase substantially in patients with hypoalbuminemia, leading to higher free valproate levels 4, 5.
- Serum albumin levels can affect the protein binding of valproic acid, resulting in increased free valproate levels in patients with hypoalbuminemia 3, 6, 7.
Clinical Implications
- In patients with hypoalbuminemia, the total serum concentration of valproic acid may not accurately reflect the free valproate levels, leading to potential toxicity or subtherapeutic effects 3, 4, 6.
- Measuring free serum valproic acid concentrations is ideal for therapeutic drug monitoring, especially in patients with hypoalbuminemia or fluctuating albumin levels 4, 5, 7.
- Equations to calculate albumin-adjusted total concentrations can be used to estimate free valproate levels, but may not always be accurate and can underestimate the measured concentrations 6, 7.
Patient-Specific Factors
- Patient-specific factors, such as weight, age, serum creatinine, and dose, may not have a clear relationship with free valproate levels in patients with hypoalbuminemia 4.
- Female patients with similar albumin levels may have higher free fractions than male patients 4.
- Critically ill patients with hypoalbuminemia may require close monitoring for signs of valproate toxicity due to the potential for high unbound fractions of valproic acid 5.