Abstract

In this study a pharmacokinetic-pharmacodynamic model is proposed for drugs with nonlinear elimination kinetics. We applied such an integrated approach to characterize the pharmacokinetic-pharmacodynamic relationship of phenytoin. In parallel, the anticonvulsant effect and the electroencephalogram (EEG) effect were used to determine the pharmacodynamics. Male Wistar-derived rats received a single intravenous dose of 40 mg · kg⁻¹ phenytoin. The increase in the threshold for generalized seizure activity (TGS) was used as the anticonvulsant effect and the increase in the total number of waves in the 11.5 to 30 Hz frequency band was taken as the EEG effect measure. Phenytoin pharmacokinetics was described by a saturation kinetics model with Michaelis-Menten elimination.V_max and K_mvalues were, respectively, 386 ± 31 μg · min⁻¹and 15.4 ± 2.2 μg · ml⁻¹ for the anticonvulsant effect in the cortical stimulation model and 272 ± 31 μg · min⁻¹ and 5.9 ± 0.7 μg · ml⁻¹ for the EEG effect. In both groups, a delay to the onset of the effect was observed relative to plasma concentrations. The relationship between phenytoin plasma concentrations and effect site was estimated by an equilibration kinetics routine, yielding mean k_e0 values of 0.108 and 0.077 min⁻¹ for the anticonvulsant and EEG effects, respectively. The EEG changes in the total number of waves could be fitted by the sigmoid E_max model, but E_max values could not be estimated for the nonlinear relationship between concentration and the increase in TGS. An exponential equation (E =E₀ +Bⁿ · Cⁿ) derived from the sigmoid E_max model was applied to describe the concentration-anticonvulsant effect relationship, under the assumption that E_maxvalues cannot be reached within acceptable electric stimulation levels. This approach yielded a coefficient (B) of 2.0 ± 0.4 μA · ml · μg⁻¹ and an exponent (n) of 2.7 ± 0.9. The derived EC₅₀value of 12.5 ± 1.3 μg · ml⁻¹ for the EEG effect coincides with the “therapeutic range” in humans.