Phenytoin Correction for Concurrent Valproic Acid

Dilantin Correction Calculator for Concurrent Depakote

Drug Level Parameters

Total phenytoin
Total valproic acid

Press 'Calculate' to view calculation results.

About This Calculator

There is a drug-drug interaction between phenytoin and valproic acid (Depakote® or Depakene®). In addition to an interaction due to drug metabolism, both drugs compete for albumin protein binding sites. With concurrent administration, the free fraction of phenytoin (percent unbound:bound) is increased. This effect is described in the "Understanding Total vs Free Phenytoin" below:

Although unbound (free) phenytoin levels can be measured by a laboratory assay, this method may not be available on-site at all institutions, or the turnaround time for a result may be so long that it limits its clinical utility. For this reason, a number of equations have been developed to mathematically "adjust" phentoin levels in patients with concurrent valproic acid.

Correction Equations

This calculator uses two published equations to adjust a total phenytoin level given a measured valproic acid level. Note that both equations generate a free (unbound) corrected phenytoin level.

May 1991 equation: 1
$$\\Corrected\;free\;PHT = (0.0792 + 0.000636*VPA)) * (Total\;PHT)$$
Haidukewych 1989 equation: 2
$$\\Corrected\;free\;PHT = (0.095 + 0.001*VPA)) * (Total\;PHT)$$

May vs Haidukewych

There is evidence to suggest that the May equation may be more appropriate for phenytoin levels measured with an HPLC assay, and Haidukewych for a TDx assay.3 In a subsequent analysis, the May equation using an HPLC assay was the most accurate equation, although this comparison was done by May et al.3

Calculator Limitations

The equations for valproic acid correction do not account for hypoalbuminemia. Although there are phenytoin corrections for hypoalbuminemia, these equations have not been evaluated in conjunction with valproic acid correction equations.

References and Additional Reading

  1. May TW, Rambeck B, Nothbaum N. Nomogram for the prediction of unbound phenytoin concentrations in patients on a combined treatment of phenytoin and valproic acid. Eur Neurol. 1991;31(1):57-60. PMID 2015840.
  2. Haidukewych D, Rodin EA, Zielinski JJ. Derivation and evaluation of an equation for prediction of free phenytoin concentration in patients co-medicated with valproic acid. Ther Drug Monit. 1989;11(2):134-9. PMID 2497562.
  3. May TW, Rambeck B, Jürges U, Blankenhorn V, Jürgens U. Comparison of total and free phenytoin serum concentrations measured by high-performance liquid chromatography and standard TDx assay: implications for the prediction of free phenytoin serum concentrations. Ther Drug Monit. 1998;20(6):619-23. PMID 9853976.


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Updated Jul 1, 2017
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