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Epilepsy Res. 2007 Mar;73(3):275-83. Epub 2007 Jan 8.

Distinct absorption characteristics of oral formulations of valproic acid/divalproex available in the United States.

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Abbott Laboratories, Abbott Park, IL 60064, USA.


Five oral formulations of valproic acid (VPA)/divalproex sodium are approved and commonly used in the US for treatment of epilepsy, mania/bipolar disorder and migraine prophylaxis. These formulations have unique pharmacokinetic and formulation characteristics and are designed to treat distinct patient populations. We compared the absorption characteristics of all five oral VPA/divalproex formulations currently available in the US. Plasma VPA concentration-time profiles, following single oral dose (250mg) administration of five VPA/divalproex formulations under fasting conditions, from three pharmacokinetic studies in healthy subjects (N=9-15 each) were compared. The five VPA/divalproex formulations demonstrated marked absorption differences. The rate of absorption, as characterized by maximum concentration (C(max)) and time to C(max) (T(max)), may be rank-ordered as: VPA syrup (34.2mg/L, 0.9h)>VPA capsule (31.4mg/L, 2.2h)>divalproex sodium sprinkle capsule (20.7mg/L, 4.0h; lag-time congruent with1h) congruent withdivalproex sodium enteric-coated delayed-release tablet (26.0mg/L, 3.4h; lag-time congruent with2h)>divalproex sodium extended-release (divalproex-ER) tablet (11.8mg/L, 19.7h). Divalproex-ER had approximately 11% lower exposure (AUC). The comparable AUC across the five formulations, when corrected for bioavailability differences, demonstrates that formulation primarily affects the drug-release and in vivo absorption of VPA. Only divalproex-ER demonstrated true sustained-release characteristics.

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