Influence of coadministered antiepileptic drugs on serum zonisamide concentrations in epileptic patients: quantitative analysis based on suitable transforming factor.

We conducted a study to clarify the most suitable transforming factor related to the daily zonisamide dose (D) providing a steady-state serum concentration (C-1) and analyzed the influences of the concomitant use of antiepileptic drugs on C, 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 as a transforming factor, led the level/dose (L/D) ratio (:C-t/(D/V-ECW)) to be independent of the patient's age and sex for the administration of ZNS alone. C, was revealed to be dependent on only one variable regarding D/V-ECW, and expressed as C-t=0.604X(D/V-ECW). 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 R-i (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 R-i 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 R-i and compared with the measured ones. The mean of prediction error was calculated as 22.9%. Our results appear valid and R-i should be available for clinical use.