A Double Weibull Input Function Describes the Complex Absorption of Sustained-Release Oral Sodium Valproate

The pharmacokinetics of valproic acid after oral administration of sustained-release formulations were studied in 12 healthy volunteers. The objective of the present study was to find an appropriate mathematical model to describe the complex drug intake process. The concentration of valproic acid in plasma was measured by HPLC. For each subject, during the input process a double peak phenomenon was observed, the plasma concentrations were fitted according to a single or a double Weibull input function, and then a first-order elimination rate was used to describe the observed data. The Weibull model was considered as an approximation 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; the 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 γ (shape) of 1.16 ± 0.66. A double Weibull input function was used for nine subjects; the mean Weibull parameters were td1= 2.35 ± 1.18 h and td2= 9.36 ± 4.47 h and γ2= 1.77 ± 2.27 and γ2= 3.68 ± 3.26. The mean half-life value of the elimination phase was 14.4 ± 4.6 h.