Analysis of the factors influencing anti-epileptic drug concentrations--valproic acid

The factors that influence valproic acid (VPA) serum concentrations and level:dose ratios were evaluated, retrospectively, on 51 consecutive routine VPA determinations from 50 chronically treated epileptic patients. The influence of co-medicated anti-epileptic drugs (phenytoin, phenobarbital, carbamazepine), alone or in combination, on total and free levels of VPA was studied. Furthermore, the possible influence of certain physiological and/or pathophysiological factors (age, weight, sex and clinical laboratory data) was considered. The total level:dose ratio was lower when VPA was given in combination with phenytoin or with carbamazepine than when VPA was given alone. The free level:dose ratio also decreased during concomitant treatment with phenytoin. The free fraction of VPA was unaltered when in combination with phenytoin or with carbamazepine, whereas it was decreased by a combination with phenytoin plus carbamazepine. As a whole, strong, positive, correlations existed between the VPA dose (mg/kg/day) and the total and free serum levels of VPA in the range of less than 15 mg/kg/day, but both levels of VPA tended to flatten out at the range of more than 15 mg/kg/day. These findings should therefore be considered when defining dosage regimens or interpreting serum drug concentrations. Stepwise multivariate regression analysis (MVR) showed that the VPA dose, simultaneous carbamazepine intake, serum glutamic oxalacetic transaminase (SGOT) and serum albumin concentration were important determinants of VPA serum concentrations.