Abstracts

Extended-release divalproex sodium (divalproex-ER) has a well-characterized plasma valproic acid (VPA) concentration-time profile following once-daily administration in patients with epilepsy (Dutta S, et.al, [italic]Epilepsy Res[/italic] 2002; Sommerville KW, et.al., [italic]Clin Drug Invest[/italic] 2003). However, information concerning relevant aspects of the biopharmaceutics of divalproex-ER after twice-daily administration, a regimen commonly employed by neurologists, is lacking. We compared the VPA concentration-time profiles of divalproex-ER dosed twice-a-day [italic]vs[/italic]. the same formulation dosed once-daily [italic]vs[/italic]. the conventional enteric-coated, delayed-release divalproex sodium (divalproex) formulation dosed four-times-a-day in patients with epilepsy concurrently treated with enzyme-inducing antiepileptic drugs (AEDs). Twenty-four patients with epilepsy, concomitantly receiving an enzyme-inducing AEDs, received the same total daily dose (1-3 g) of the following three regimens each for 14 consecutive days: divalproex-ER once every AM, divalproex-ER every 12 hours, and conventional divalproex every 6 hours. The open-label, multiple-dose, randomized study had a three-period crossover design. Complete data was collected for twenty-two patients. For day 14 of each regimen, the steady-state total plasma VPA mean maximum concentration (Cmax, mg/L), minimum concentration (Cmin, mg/L), exposure (AUC0-24, mg.h/L) [amp] degree of peak-trough fluctuation (DFL) were 71.7, 45.6, 1418 [amp] 0.46 for divalproex-ER every 12 hours, 71.4, 39.5, 1366, 0.59 for divalproex-ER once daily, and 82.8, 41.0, 1440, 0.71 for conventional divalproex every 6 hours. VPA Cmin values for twice-daily divalproex-ER were significantly higher than those for once-daily divalproex-ER (p = 0.043). As expected, once-daily divalproex-ER Cmin values were not different from conventional divalproex administered every 6 hours. The DFL in total plasma VPA concentrations was significantly less with both daily (16.9% less) and twice-daily (35.2% less) regimens of the divalproex-ER formulation compared to divalproex given every 6 hours (p[underline][lt][/underline] 0.024), primarily because of significant lowering of the Cmax (p [lt] 0.001). The DFL for twice-daily divalproex-ER administration was statistically distinguishable (22% less) from once-daily administration (p=0.02). Adverse effects were mild in severity among the three regimens. This study reconfirms that divalproex-ER administered once-daily adequately maintains trough steady-state plasma VPA concentrations, despite the presence of enzyme-inducing comedications in patients with epilepsy. The DFL in peak-trough plasma VPA concentrations with divalproex-ER can be minimized with once-daily administration, and more so with twice-daily administration, compared to conventional enteric-coated divalproex given every 6 hours. (Supported by Abbott Labs.)