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

SummaryFive 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 (250 mg) 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 (Cmax) and time to Cmax (Tmax), may be rank-ordered as: VPA syrup (34.2 mg/L, 0.9 h) > VPA capsule (31.4 mg/L, 2.2 h) > divalproex sodium sprinkle capsule (20.7 mg/L, 4.0 h; lag-time ≅ 1 h) ≅ divalproex sodium enteric-coated delayed-release tablet (26.0 mg/L, 3.4 h; lag-time ≅ 2 h) > divalproex sodium extended-release (divalproex-ER) tablet (11.8 mg/L, 19.7 h). Divalproex-ER had ∼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.