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. doi: 10.1097/00007691-198903000-00003.


The relationship between free phenytoin fraction (F-PHT-F) and valproic acid (VPA) was studied under two conditions: (a) in serum samples from 43 institutionalized patients (212 serial data points) at plateau steady state, and (b) in plasma samples from 50 outpatients coming for regular visits to our clinic throughout the day. Results for both groups led to identical linear regression equations relating F-PHT-F to VPA: F-PHT-F = 0.095 + 0.001 (VPA). Nevertheless, as expected, the resulting equation gave an unreliable prediction of F-PHT-F due to a variable physiological matrix. Substituting the parameter F-PHT-F by its equivalent (F-PHT/PHT) gave the equation F-PHT = [0.095 + 0.001 (VPA)] PHT. The predictive power of this equation was evaluated by the comparison of obtained and predicted F-PHT concentrations. For the combined patient group (n = 93), an excellent agreement (r = 0.972 and F = 999.9; p less than 0.001) was obtained. Although the empirically derived constants of the equation are not unique and may vary depending on the conditions of different methodologies, the fundamental relationship has been established and can be used to reliably predict F-PHT concentration from plasma VPA and PHT concentrations.

MeSH terms

  • Adult
  • Aged
  • Drug Therapy, Combination
  • Epilepsy / blood*
  • Epilepsy / drug therapy
  • Female
  • Humans
  • Male
  • Mathematics
  • Middle Aged
  • Phenytoin / blood*
  • Phenytoin / therapeutic use
  • Retrospective Studies
  • Valproic Acid / blood*
  • Valproic Acid / therapeutic use


  • Valproic Acid
  • Phenytoin