Modelling of the pharmacodynamic interaction between phenytoin and sodium valproate |
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Authors: | O E Della Paschoa R A Voskuyl M Danhof |
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Affiliation: | 1.Division of Pharmacology, Leiden/Amsterdam Centre for Drug Research, P.O. Box 9503, 2300 RA Leiden, The Netherlands;2.Instituut voor Epilepsie Bestrijding (Meer en Bosch), P.O. Box 21, 2100AA, Heemstede, The Netherlands |
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Abstract: | - 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 μg ml−1. A control group received only the infusion of VPA. The increase in the threshold for generalized seizure activity (ΔTGS) 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 μg min−1 and 7.8±2.4 μg ml−1 in the absence of VPA and 562±40 μg min−1 and 15.6±0.9 μg 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 μg 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.
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Keywords: | Phenytoin sodium valproate drug interaction cortical stimulation PK/PD modelling |
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