Influence of Coadministered Antiepileptic Drugs on Serum Zonisamide Concentrations in Epileptic Patients: Quantitative Analysis Based on Suitable Transforming Factor

摘要

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_t) and analyzed the influences of the concomitant use of antiepoileptic drugs on C_t 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 (V_(ECW)) 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_t was revealed to be dependent on only one variable regarding D/V_(ECW) and expressed as C_t = 0.604 * (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.