Prediction of steady-state concentrations of valproic acid as determined from single plasma concentrations after the first dose

Abstract

A mathematical equation that predicts the maintenance dose needed to achieve a desired steady-state plasma concentration (Css) for first-order drugs from a single plasma concentration drawn after a single dose was tested for valproic acid. Six healthy volunteers received a single oral 500-mg dose of valproic acid and plasma concentrations were determined at 0, 1, 2, 4, 6, 8, 10, 24, and 32 hours. Each subject then received 750 mg of valproic acid daily in three divided doses for four days and a Css was determined. The equation was rearranged to predict the Css of valproic acid from plasma concentrations drawn at 1, 2, 4, 6, 8, and 10 hours after the single dose of valproic acid, using individually determined and mean terminal rate constant (k) values. The predicted Css were then compared with the actual Css. There was no difference in the predicted and actual Css using plasma concentrations collected at 6, 8, or 10 hours regardless of the derivation of the k values. The four-hour concentration predicted a lower Css if the mean (rather than the individual) k values were used. The one- and two-hour concentrations were not accurate predictors. While a 6-, 8-, or 10-hour plasma concentration would be adequate for predicting the Css, the 10-hour concentration had the least difference between the predicted and actual values. The time and cost of titrating valproic acid to a desired Css may be decreased by using this mathematical equation to predict the necessary maintenance dose.