Abstracts

Several oral formulations of valproic acid (VPA) are commonly used for treatment of epilepsy, mania associated with bipolar disorder and prophylaxis of migraine headache. These VPA formulations have distinct pharmacokinetic and formulation characteristics and are designed to treat distinct patient populations depending on the clinical need to quickly attain higher concentrations, balanced against the potential side effect profiles. To date, these formulations have not been directly compared. The purpose of this evaluation was to compare the absorption characteristics of 5 commonly used oral formulations of VPA. Plasma VPA concentration-time profiles, following single oral dose administration of 5 VPA formulations under fasting conditions, from 4 pharmacokinetic studies in healthy subjects were compared: VPA syrup (N=12) and capsule (N=12), and divalproex sodium sprinkles capsule (N=10), delayed-release (DR) enteric-coated tablet (N=10), and extended-release (ER) tablet (N=15). VPA pharmacokinetic parameters were calculated using non-compartmental methods. The syrup formulation demonstrated the most rapid absorption with the highest Cmax and shortest Tmax. In general, the rate and extent of absorption were similar for capsule, sprinkles capsule, and DR tablet; but could be rank-ordered as capsules [gt] sprinkles [cong] DR tablets. DR tablets exhibited a 1-2 hr absorption lag-time, followed by rapid absorption at a rate similar to that of capsule and sprinkles capsule. ER tablet, designed to deliver drug at a slow zero-order rate over [gt]18 hrs, had the slowest absorption with the lowest Cmax and longest Tmax. Mean exposure (AUC), apparent oral clearance (CL/F), and apparent volume of distribution (V/F) were comparable across all 5 formulations and ranged from 785-994 mg[bull]h/L, 0.515-0.653 L/h, and 9.78-13.8 L, respectively. For a 500 mg single dose, the mean Cmax (mg/L) and Tmax (h) values were 63.8 and 0.7 for syrup, 53.3 and 1.8 for capsule, 41.4 and 4.0 for sprinkles capsule, 51.9 and 3.4 for DR tablet, and 23.5 and 19.7 for ER tablet, respectively. The 5 VPA formulations demonstrated distinct absorption characteristics. The rate of absorption, as characterized by Cmax and Tmax, may be rank-ordered as VPA syrup [gt] VPA capsule [gt] divalproex sprinkles capsule [cong] divalproex-DR tablet [gt] divalproex-ER tablet. ER is the only formulation exhibiting true sustained-release characteristics. (Supported by Abbott Laboratories.)