When do you check Valproic Acid (VPA) levels in patients on valproic acid therapy?

From the Guidelines

Valproic acid (VPA) levels should be checked 4-7 days after starting therapy or after dose adjustments, and then periodically during maintenance therapy, typically every 3-6 months in stable patients. This recommendation is based on the need to maintain a therapeutic range of 50-100 μg/mL (350-700 μmol/L) to ensure efficacy while minimizing toxicity 1. The study by Bauer et al. highlights the importance of monitoring VPA levels, as it discusses the endocrine effects of valproate, including weight gain, polycystic ovaries, and hyperandrogenism, which can be mitigated by adjusting the dose or switching to a different medication 1.

When checking VPA levels, it is essential to consider the timing of the sample collection, with trough levels drawn just before the next scheduled dose. More frequent monitoring may be necessary in certain situations, such as:

• When clinical response is inadequate
• When medication adherence is questionable
• When side effects occur
• During pregnancy
• When adding or removing medications that might interact with valproic acid
• In patients with liver disease, elderly patients, and children, who may require more frequent monitoring due to altered metabolism.

The rationale for monitoring VPA levels is that valproic acid has a narrow therapeutic window, and levels correlate with both efficacy and toxicity 1. Subtherapeutic levels may lead to breakthrough seizures or mood instability, while supratherapeutic levels can cause adverse effects ranging from gastrointestinal distress to serious hepatotoxicity or pancreatitis. Therefore, regular monitoring of VPA levels is crucial to ensure the safe and effective use of valproic acid therapy.

From the FDA Drug Label

Plasma Levels and Clinical Effect The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the clearance of the drug Thus, monitoring of total serum valproate cannot provide a reliable index of the bioactive valproate species.

Valproic Acid (VPA) levels should be checked when:

• Epilepsy: The therapeutic range is commonly considered to be 50 to 100 μg/mL of total valproate.
• Clinical management: In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured.
• Periodic monitoring: Periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy.
• Surgery: Patients receiving valproic acid should be monitored for platelet count and coagulation parameters prior to planned surgery.
• Therapy initiation: Platelet counts and coagulation tests are recommended before initiating therapy and at periodic intervals. 2 2

From the Research

Monitoring Valproic Acid (VPA) Levels

To determine when to check VPA levels in patients on valproic acid therapy, several factors must be considered, including the patient's condition, the dosing regimen, and potential interactions with other drugs.

• VPA levels should be monitored carefully due to the wide variation in total and free levels, especially in patients taking multiple drugs 3.
• The time since the last dose also affects VPA levels, with minimum levels typically occurring at morning predose and maximum levels at postdose testing 3.
• Nonlinear binding of VPA causes large increases in free levels as total VPA concentration rises, making it essential to monitor both free and total VPA levels 3.
• In patients receiving continuous infusion VPA therapy, serum concentration variability can be mitigated, and steady-state serum concentrations can be more consistently achieved 4.
• The frequency of checking VPA levels may depend on the specific dosing regimen, with more frequent monitoring needed for patients receiving intermittent bolus dosing compared to continuous infusion 4.
• Age, induction status, and formulation can also impact VPA pharmacokinetics, making individualized monitoring and dosing adjustments necessary 5.
• Patients at high risk of VPA hepatotoxicity, such as young children and those taking polytherapy, may require more frequent monitoring of VPA levels and liver function tests 6.