Abstract
We conducted a study to clarify the most suitable transforming factor related to the daily zonisamide dose (D) providing a steady-state serum concentration (Ct) and analyzed the influences of the concomitant use of antiepileptic drugs on Ct quantitatively. Data obtained by routine therapeutic drug monitoring from a total of 175 epileptic patients treated with the multiple oral administrations of zonisamide (ZNS) as a powder/tablets, were used for the analysis. Employing the extracellular water volume (VECW) as a transforming factor, led the level/dose (L/D) ratio (:Ct/(D/VECW)) to be independent of the patient's age and sex for the administration of ZNS alone. Ct was revealed to be dependent on only one variable regarding D/VECW and expressed as Ct=0.604×(D/VECW). Phenytoin (PHT) significantly lowered (p<0.01) the L/D ratio to 0.76 of the value for ZNS alone. For a more detailed analysis, we defined the parameter Ri (i=1, 2, …, 6) as an alteration ratio, representing the influence of each antiepileptic drug on the L/D ratio of ZNS alone. A model based on the assumption that each Ri value was independent from one another and multiplicative, was adopted. The analysis clarified that phenobarbital, valproic acid, carbamazepine, and PHT significantly lowered (p<0.05) the L/D ratio of ZNS to 0.849, 0.865, 0.846, and 0.804, respectively. In the case of the addition or discontinuance of concomitant treatment with antiepileptic drugs in the same patient, the estimated L/D ratios were calculated using the value of each Ri and compared with the measured ones. The mean of prediction error was calculated as 22.9%. Our results appear valid and Ri should be available for clinical use.
