title: 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.
abstract: Divalproex sodium extended-release (divalproex-ER), administered once-daily, maintains plasma valproic acid (VPA) concentrations for 24h, 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 (C(max)). 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 C(max)<100mg/L; >or=2000 mg produced mean C(max)>or=125 mg/L. Mean divalproex C(min) was approximately 50 mg/L at two of four doses tested, whereas mean ER C(min) 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 (>or=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.
authors.affiliation: Global Pharmaceutical Research & Development Neuroscience, Abbott Laboratories, Abbott Park, IL 60064-6075, USA. Ronald.Reed@abbott.com
authors.forename: Ronald Charles
authors.initials: RC
authors.lastname: Reed
authors.forename: Sandeep
authors.initials: S
authors.lastname: Dutta
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
mesh_terms: D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood; D019540:Area Under Curve; D003198:Computer Simulation; D003692:Delayed-Action Preparations / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004827:Epilepsy / Q000188:drug therapy*; D006801:Humans; D008954:Models, Biological; D013997:Time Factors; D014635:Valproic Acid / Q000008:administration & dosage* / Q000097:blood
chemical_list: D000927:Anticonvulsants; D003692:Delayed-Action Preparations; D014635:Valproic Acid