血清中抗てんかん薬濃度に及ぼす併用抗てんかん薬の影響 —至適換算因子に基づく定量的解析—

抄録

  We conducted a study to clarify the most suitable transforming factor related to the daily dose of antiepileptic drugs (D) providing a steady-state serum concentration (C_t) and analyzed the influences of the concomitant use of antiepileptic drugs on C_t quantitatively. Data obtained by routine therapeutic drug monitoring from epileptic patients treated with the multiple oral administration of valproic acid (VPA), carbamazepine (CBZ), zonisamide (ZNS), phenobarbital (PB), and phenytoin (PHT) were used for the analysis. Employing the ideal body weight or the extracellular water volume as a transforming factor, allowed the level/dose (L/D) ratio to be independent of the patient's age and gender for monotherapy with VPA or CBZ, ZNS, PB, and PHT, respectively. Each C_t was revealed to be dependent on only one variable in terms of the transformed daily dose (D′). C_t was proportional to the power function of D′ for VPA and CBZ and was linearly proportional to D′ for ZNS and PB. The L/D ratio is expressed as a linear function of C_t for PHT. For a detailed analysis of the influences of the coadministered antiepileptic drugs, we defined the parameter as an alteration ratio, representing the influence of each antiepileptic drug on the C_t of VPA and CBZ alone, and on the L/D ratio of ZNS and PB alone, respectively. A model based on the assumption that each value of an alteration ratio was independent from one other and multiplicative for VPA, CBZ, and ZNS, and that the coadministered drug inhibited the drug-metabolizing enzyme competitively for PB, was adopted. The Michaelis-Menten kinetic model was adopted for PHT. The analysis clarified that CBZ, PB, and PHT significantly lowered (P<0.05) C_t to 0.81, 0.88, and 0.83 compared with the value of VPA alone, that PB and PHT significantly lowered C_t to 0.77 and 0.71 compared with the value of CBZ alone, and that VPA, CBZ, PB, and PHT significantly lowered the L/D ratio of ZNS alone to 0.87, 0.85, 0.85, and 0.80, respectively. VPA, CBZ, and PHT significantly increased (P<0.05) the L/D ratio of PB to 1.47, 1.18, and 1.19, respectively. The daily PHT dose was decreased to 0.89, 0.91, 0.90, and 0.84 the dose of PHT alone to maintain C_t in the therapeutic range when VPA, CBZ, ZNS, and PB were coadministered, respectively. In the case of the addition or discontinuance of concomitant treatment with antiepileptic drugs in the same patient, the estimated C_t values were calculated using the value of each alteration ratio and compared with the measured ones. Each mean of prediction error was about 20%. Our results appear valid and these alteration ratios should be available for clinical use.