PHARMACOKINETICS OF VALPROATE AFTER MULTIPLE-DOSE ORAL AND INTRAVENOUS-INFUSION ADMINISTRATION - GASTROINTESTINAL-RELATED DIURNAL-VARIATION

A randomized, crossover study was conducted in healthy male volunteers to assess the diurnal variation in the steady-state pharmacokinetics of valproate after multiple 250-mg oral and intravenous infusion doses after an intravenous 750-mg loading dose. Multiple blood samples were collected throughout each 168-hour study period, and plasma valproate concentrations were quantitated using a gas chromatographic technique . Within-regimen comparisons indicated statistically significant diffe rences for mean steady-state peak (C-max) and trough (C-min) plasma co ncentrations and area under the plasma concentration-versus-time curve (AUC) between the second end third doses on day 4 after oral dosing, indicating a diurnal variation in the rate of valproate absorption fro m the delayed-release tablet preparation. Between-regimen steady-state comparisons of pharmacokinetic parameters revealed some significant d ifferences in mean time to C-max (T-max), C-max, C-min, AUC, and total body clearance for respective day-4 dosing intervals, but not for the entire day 4, except for C-min and T-max. Mean elimination rate const ant and half-life did not significantly differ between the regimens. T he regimens were bioequivalent at steady state, as assessed by 90% con fidence intervals (two one-sided test procedures) for C-max, C-min, an d AUC, with similarity in degrees of fluctuation {(C-max-C-min)/C-aver age}. Despite the presence of diurnal variation in valproate absorptio n after oral dose administration, the steady-state plasma concentratio n-versus-time profile was well maintained by both regimens within the accepted therapeutic range of 50 to 100 mu g/mL.