Oral/intravenous maintenance dosing of valproate following intravenous loading: a simulation

Valproic acid (VPA) has a narrow therapeutic range (50-100 mg/l) and exhibits nonlinear protein binding. Additionally, VPA pharmacokinetics are dependent on age, induction status, and formulation; so titration and dosing vary between individuals. The aim of these simulations was to determine optimal intravenous (i.v.) loading dose, and i.v. and oral VPA maintenance regimens. A 5-min 15 mg/kg loading dose resulted in total and free plasma VPA concentrations of similar to65 and 7.5 mg/l in children, and similar to80 and I I mg/l in adults, I h after the infusion; induction status had little effect. For uninduced children and adults, 7.5 and 3.5 mg/kg q6h i.v. valproate sodium, initiated 6 h after loading dose maintains therapeutic plasma VPA concentrations. The rapid decline of plasma VPA concentrations following an i.v. loading dose in combination with the delayed initial absorption of drug from delayed-release divalproex sodium tablets warrant beginning q12h oral maintenance regimens of delayed-release divalproex sodium within 2 h of a loading dose in the uninduced population. Plasma VPA concentrations can be sustained in the therapeutic range using once-daily maintenance regimens of extended-release divalproex. sodium tablets if initiated concurrently with i.v. loading dose in the uninduced population. A two-fold higher i.v. and oral maintenance regimen dose may be required in induced patients. (C) 2002 Elsevier Science B.V. All rights reserved.