When should a trough valproic acid (valproate) level be drawn for therapeutic drug monitoring?

When to Draw Valproic Acid Levels

Draw valproic acid levels as a trough (immediately before the next dose) after reaching steady-state, which occurs at least 5 half-lives after starting therapy or any dose change—typically 3-5 days for standard formulations.

Timing Based on Formulation

Standard/Delayed-Release Formulations

• Collect blood immediately before the morning dose (12-24 hours after the last dose, depending on dosing frequency) 1
• Steady-state is reached approximately 1 week after stable daily dosing for most patients 1
• The trough represents the lowest concentration and is the standard reference point for therapeutic monitoring 2

Extended-Release (ER) Formulations

• For morning dosing: Draw 21-24 hours after the dose (immediately before next dose), which reflects true trough levels within 3% accuracy 3
• For evening dosing: Optimal timing is 18-21 hours post-dose (e.g., if dosed at 8 PM, draw between 2-5 PM the next day), which yields values only 3-13% higher than true trough 3
• Avoid drawing 3-15 hours post-dose (around peak time), as this can overestimate trough levels by 18-25% and lead to inappropriate dose adjustments 3

Key Timing Principles

Steady-State Requirements

• Wait at least 5 drug half-lives after any dose change before drawing levels 1
• For valproic acid with a half-life of approximately 14 hours in bipolar patients 2, this translates to roughly 3-5 days
• Both dose modifications and addition of interacting medications (especially enzyme inducers/inhibitors) require waiting for new steady-state 1

Clinical Situations Requiring Levels

• Initial therapeutic monitoring: After 1 week of stable dosing 1
• Suspected toxicity: Can draw at any time, though peak levels (4 hours post-dose for standard formulations) may be more informative 2
• Breakthrough seizures or loss of efficacy: Draw trough to assess subtherapeutic levels 4
• Drug interaction concerns: Carbapenems (meropenem, imipenem, ertapenem) dramatically reduce valproic acid levels and warrant urgent level checking 4

Common Pitfalls to Avoid

• Don't draw too early after dose changes: Levels drawn before steady-state (< 5 half-lives) will not accurately reflect therapeutic concentrations 1
• Don't draw at random times with ER formulations: The timing significantly impacts interpretation, with peak concentrations occurring 3-15 hours post-dose being 18-25% higher than trough 3
• Don't ignore formulation differences: Standard formulations peak at approximately 4 hours, while ER formulations have controlled, near zero-order absorption with different timing considerations 3, 2
• Don't delay monitoring when unexpected side effects occur: In cases of suspected toxicity, immediate level checking is warranted regardless of timing since last dose 1

Target Therapeutic Ranges

• Seizure disorders: 50-100 μg/mL 4
• Mood stabilization/impulsive behavior: 40-90 μg/mL 5
• Trough concentrations below 50 μg/mL are generally subtherapeutic for seizure control 6