Once-daily dosing is appropriate for extended-release divalproex over a wide dose range, but not for enteric-coated, delayed-release divalproex: Evidence via computer simulations and implications for epilepsy therapy

Divalproex sodium extended-release (divalproex-ER), administered once-daily, maintains plasma valproic acid (VPA) concentrations for 24 h, whereas enteric-coated, delayed-release divalproex sodium (divalproex) requires multiple-daily doses to do the same. We hypothesize that a once-daily divalproex regimen should not be administered to epilepsy patients requiring high total daily doses, e.g., 35.6-56 mg/kg/day, due to the potential for high (>125 mg/L) maximum VPA concentrations (Cmax). We examined the impact of once-daily dosing, divalproex vs. divalproex-ER, on steady-state plasma VPA concentration-time profiles at commonly used doses in monotherapy (uninduced) and polytherapy (hepatic enzyme-induced) virtual adult patients. Only the 1125 mg once-daily divalproex dose had mean Cmax < 100 mg/L; ≥2000 mg produced mean Cmax ≥ 125 mg/L. Mean divalproex Cmin was ∼50 mg/L at two of four doses tested, whereas mean ER Cmin was >73 mg/L at all doses tested. Once-daily divalproex peak-trough fluctuation was 4.4-6.2-fold greater than once-daily divalproex-ER. We predict that excursions beyond the conventional recommended VPA plasma concentration range will commonly occur with high total mg daily doses (≥2000 mg) of enteric-coated divalproex, if dosed once-daily, potentially producing clinical toxicity. This divalproex formulation should not be dosed once-daily at high total mg daily doses due to this risk. Divalproex-ER is the appropriate formulation for administration on a once-daily basis, especially if large total mg/day doses are required for the control of seizure activity.