てんかん患児のバルプロ酸単剤治療における血清遊離型濃度に関する臨床薬理学的研究

Abstract

The VPA total level (T value), the free level (F value), and the free fraction (FF) were measured in 74 epileptic children under valproic acid (VPA) monotherapy. The relationship between the T value, blood collection time, therapy duration, serum free fatty acid, clinical features, F value and FF were then studied. Blood was taken either before the morning (pre-breakfast) administration of medicine (Cmin), 2-3 hours after the post-breakfast administration (Cmax), or both. The subjects were divided into one Cmin. and one Cmax. group. The results of serum VPA measurement revealed that T values in the Cmin. group ranged from 23.0 micrograms/ml to 113.0 micrograms/ml (average: 50.0 +/- 16.2 micrograms/ml), F values from 2.0 micrograms/ml to 16.0 micrograms/ml (6.0 +/- 2.7 micrograms/ml) and FF from 5.9% to 21.7% (11.8 +/- 3.8%). In the Cmax. group, T values ranged from 41.0 micrograms/ml to 163.0 micrograms/ml (80.5 +/- 24.3 micrograms/ml), F values from 3.7 micrograms/ml to 22.8 micrograms/ml (10.0 +/- 4.2 micrograms/ml) and FF from 7.1% to 22.2% (12.2 +/- 3.3%). There was no difference in FF between the two groups. In both groups, T and F values significantly and positively correlated and FF was not affected by age or VPA therapy duration. However, FF varied in the early stage of medication. In individual cases with no seizures and receiving constant doses, the longer the period of medication, the greater the decrease in FF. Although free fatty acid was concurrently measured in some cases, it did not correlate with the F value or the FF. In 45 cases, changes in the FF were followed in both groups on the same day, but no general tendencies were noted. Diurnal fluctuation was studied in 4 cases. Significance of the clinical features was evaluated. The subjects were then classified by seizure type for group comparison and no differences in the FF among the different types were observed. During the follow-up period, 5 cases had seizures, but when their serum levels were compared with those of members of both groups, the T values did not differ. The F values and the FF in the 5 cases were below the mean values of the two groups. These findings suggest that when factors affecting VPA protein binding are expected to be present or when seizures cannot be controlled despite a sufficient T value in the blood, the F value measurement is of particular importance.