A DOUBLE WEIBULL INPUT FUNCTION DESCRIBES THE COMPLEX ABSORPTION OF SUSTAINED-RELEASE ORAL SODIUM VALPROATE

The pharmacokinetics of valproic acid after oral administration of sus tained-release formulations were studied in 12 healthy volunteers. The objective of the present study was to find an appropriate mathematica l model to describe the complex drug intake process. The concentration of valproic acid in plasma was measured by HPLC. For each subject, du ring the input process a double peak phenomenon was observed, the plas ma concentrations were fitted according to a single or a double Weibul l input function, and then a first-order elimination rate was used to describe the observed data. The Weibull model was considered as an app roximation of the overall process. The mean peak plasma concentration, 34.6 +/- 8.9 mg/L, was reached after 8.6 +/- 2.7 h. A single Weibull function adequately described the observed data for three subjects; th e mean Weibull parameters were td (the time necessary to transfer 63% of the administered drug into the systemic circulation) of 7.87 +/- 3. 53 h and gamma (shape) of 1.16 +/- 0.66. A double Weibull input functi on was used for nine subjects; the mean Weibull parameters were td(1) = 2.35 +/- 1.18 h and td(2) = 9.36 +/- 4.47 h and gamma(1) = 1.77 +/- 2.27 and gamma(2) = 3.68 +/- 3.26. The mean half-life value of the eli mination phase was 14.4 +/- 4.6 h.