Abstracts

Depakote[reg] (or divalproex, dvpx) is a twice daily (BID) preparation for valproic acid (VPA). Depakote[reg] extended-release (dvpx-ER) is a new preparation designed for once daily administration (QD). There is a trend among some clinicians to prescribe dvpx-ER BID, concurrent with other AEDs given BID. There is a question whether BID regimens of the two preparations are equivalent in terms of the effect of missed or delayed doses on VPA concentrations. This study investigates the effect of missed and replacement doses on dvpx and dvpx-ER; both given BID. To account for the lower bioavailability of dvpx-ER (F=0.89 vs. F=1 for dvpx); 1250 mg (BID) of dvpx-ER was compared to 1000 mg (BID) of dvpx. 100 subjects were simulated for each poor compliance scenario with either one or two delayed or missed doses from schedule. Un-induced state (adults, t[sub]1/2 [/sub]=14 h) was assumed. Unbound (C[sub]u[/sub]) and total (C[sub]tot[/sub]) VPA levels were determined to assess the % of subjects that had concentrations in the sub therapeutic range (C[sub]u[/sub] [lt]5 mg /l and C[sub]tot [/sub][lt]50 mg/l), time spent in the sub therapeutic range or time at risk (h); and % of subjects in the toxic range (C[sub]tot[/sub][gt]150 mg/l). One missed or delayed dose at various times didn[rsquo]t result in sub therapeutic or toxic (in case of replacement doses) VPA concentrations for either preparation. Results for two delayed doses are shown below.[table1] Dvpx and dvpx-ER, both given BID, are equivalent in terms of the effect of poor compliance on VPA concentrations, provided that dvpx-ER dose is 20% higher than dvpx. Since VPA has a relatively short half-life, twice-daily administration seems to offer protection from sub therapeutic levels if one dose is missed. Not more than 24% (dvpx) or 20% (divalproex-ER) of subjects will have sub therapeutic concentrations if two doses are taken 12 h after the 2^nd missed dose. There is no risk of toxicity if two doses are replaced. (Supported by Abbott Labs)