Aging Variabilities of Level‐Dose Relationship in Antiepileptic Monopharmacy—with Reference to Drug Interaction between Mono‐ and Bipharmacy

: The influences of age, dose and comedication on the dose-level relationship were investigated using the ratio of plasma level to dose per body weight (/μg/ml/mg/ kg/day) as an index in patients who had received the therapeutic doses of antiepileptic drug(s) for a long term. Samples of the blood concentrations were taken from 1,922 patients ranging in age from one to 40: 1,567 measured values were obtained under medication with pheno-barbital (PB), phenytoin (PHT), carbamazepine (CBZ) or valproate (VPA) alone, and 2,201 under medication with any two of the above-mentioned antiepileptic drugs. 1)  With regard to PB, PHT, CBZ and VPA, when used alone, the L/D ratio was the lowest in the youngest age group, increased toward the latter half of teens, reached a peak at about age 20 and slightly decreased in the rest between the 20s and 30s. The age when the L/D ratio changes with aging is consistent with the age when the body weight of children obviously increases. As a result, during such a term, the fairly constant blood concentration can be maintained without overtly changing the daily dose. 2)  In the same age group given a single antiepileptic drug, the L/D ratio for PHT steeply increased at the dose of 4 in adults or 5 mg/kg/day in children, while the ratio rather decreased for CBZ and VPA. Clinical considerations should be paid to the fact that there was a non-linear relationship between the dose and the plasma concentration not only of PHT but of CBZ and VPA, and that the turning points were all within the range of therapeutic doses. Namely, that the plasma concentration of PHT is liable to reach a toxic level if the dose is slightly over the critical dose is well known. On the contrary, the innocent increase in the CBZ or VPA dosage only with the aim of obtaining the so-called therapeutic concentration is not always a rational plan of medication because of the nature of the reversed non-linear relationship between these two drugs. 3)  As regards the interaction of the two antiepileptic drugs, PHT showed no definite tendency with any partner drug; PB showed an increase in the L/D ratio when used in combination with PHT, CBZ or VPA; and CBZ and VPA showed decreases in the L/D ratio when used in combination, regardless of a partner drug. These findings should be borne in mind when we have to deal with polytherapy.