Modelling of the pharmacodynamic interaction between phenytoin and sodium valproate

Treatment of epilepsy with a combination of antiepileptic drugs remains the therapeutic choice when monotherapy fails. In this study, we apply pharmacokinetic-pharmacodynamic modelling to characterize the interaction between phenytoin (PHT) and sodium valproate (VPA). Male Wistar rats received a 40 mg kg(-1) intravenous dose of PHT over 5 min either alone or in combination with an infusion of VPA resulting in a steady-state concentration of 115.5+/-4.9 microg ml(-1). A control group received only the infusion of VPA. The increase in the threshold for generalized seizure activity (ATGS) was used as measure of the anticonvulsant effect. PHT pharmacokinetics was described by a pharmacokinetic model with Michaelis-Menten elimination. The concentration-time course and plasma protein binding of PHT were not altered by VPA. The pharmacokinetic parameters Vmax and Km were, respectively, 294+/-63 microg min(-1) and 7.8+/-2.4 microg ml(-1) in the absence of VPA and 562+/-40 microg min(-1) and 15.6+/-0.9 microg ml(-1) upon administration in combination with VPA. A delay of the onset of the effect relative to plasma concentrations of PHT was observed. The assessment of PHT concentrations at the effect site was based on the effect-compartment model, yielding mean ke0 values of 0.128 and 0.107 min(-1) in the presence and absence of VPA, respectively. A nonlinear relationship between effect-site concentration and the increase in the TGS was observed. The concentration that causes an increase of 50% in the baseline TGS (EC50%TGS) was used to compare drug potency. A shift of EC50%TGS from 13.27+3.55 to 4.32+/-0.52 microg ml(-1) was observed upon combination with VPA (P<0.01). It is concluded that there is a synergistic pharmacodynamic interaction between PHT and VPA in vivo.