Is a trough level drawn 12 hours after the last dose of a medication (e.g. valproate) a reliable measure of its trough concentration?

Trough Level Drawn 12 Hours After Last Dose of Valproate

A trough level drawn 12 hours after the last dose of valproate is not a reliable measure of its true trough concentration, as valproate's half-life ranges from 9-18 hours, meaning the true trough would occur closer to the next scheduled dose.

Understanding Trough Levels and Timing

Trough levels are intended to measure the lowest concentration of a medication in the bloodstream before the next dose is administered. For valproate, the timing of this measurement is critical:

• Valproate has a half-life of approximately 9-16 hours in adults on monotherapy 1
• The elimination half-life can be shorter (5-12 hours) in patients taking enzyme-inducing medications 2
• For accurate trough measurements, blood should be drawn immediately before the next scheduled dose

Why 12-Hour Draws Are Problematic

Drawing a level at 12 hours after the last dose when the dosing interval is longer (typically 24 hours for once-daily dosing or 12 hours for twice-daily dosing) will not capture the true trough concentration:

• If the patient is on once-daily dosing, a 12-hour sample would represent a mid-interval level, not a trough
• If on twice-daily dosing, the 12-hour sample would be appropriate only if drawn immediately before the next dose

Proper Timing for Trough Level Measurement

For medications like valproate, the timing of blood sample collection is crucial:

• For once-daily dosing: Draw the sample immediately before the next scheduled dose (approximately 24 hours after the previous dose)
• For twice-daily dosing: Draw the sample immediately before the next dose (approximately 12 hours after the previous dose)
• For three-times-daily dosing: Draw the sample immediately before the next dose (approximately 8 hours after the previous dose)

Clinical Implications

Incorrectly timed "trough" measurements can lead to:

1. Overestimation of the true trough concentration
2. Inappropriate dose adjustments
3. Potential therapeutic failure or toxicity

Guidance from Clinical Guidelines

The AGNP-TDM Expert Group consensus guidelines emphasize that TDM should be performed at the time of minimal drug concentration (true trough level) 3. This is essential for proper interpretation of the results.

Similarly, in antimicrobial monitoring, guidelines for drugs like amikacin specifically state that trough levels should be drawn predose 3, reinforcing the principle that trough measurements must be taken immediately before the next scheduled dose.

Trough:Peak Ratio Considerations

The concept of trough:peak ratio further illustrates why timing matters:

• The trough:peak ratio provides an index of how well a drug's effect is sustained over the dosing interval 4
• This ratio is determined from the blood pressure reduction at trough (end of dose interval, before next dose) relative to the reduction at peak effect 4
• The FDA defines trough as the measurement taken just before the next dose 5

Practical Recommendation

For accurate valproate monitoring:

• Always draw blood samples immediately before the next scheduled dose
• Document the exact time of the last dose and the blood draw
• Consider the patient's dosing schedule (once-daily, twice-daily) when interpreting results
• Be aware that valproate's protein binding is concentration-dependent, which affects interpretation of total valproate levels 1

If a level was drawn 12 hours after the last dose but the patient is on a once-daily regimen, this should not be considered a true trough level and should be interpreted with caution.