Abstracts

Divalproex extended-release (ER) is a once daily (QD) preparation for valproic acid (VPA) that was developed to improve compliance over the twice-daily (BID) divalproex delayed-release (DR). There is a concern that a missed or delayed dose from ER QD has higher potential for sub therapeutic levels than DR BID. Further, VPA exhibits non-linear binding to plasma proteins; the effect of missed and/or delayed doses is under-estimated when [italic]total [/italic]VPA levels are used for monitoring. There is a need to characterize the effect of different patterns of poor compliance on ER (QD) and DR (BID). Poor compliance scenarios for ER QD (1000 mg or 2500 mg) included 1) One dose taken 6 h, 12 h, 18 h, 24 h (missed dose, no make-up dose), 24 h (two doses, dose double-up) late from schedule; and 2) Two doses taken 6 h, 12 h, 18 h and 24 h after 2^nd missed dose. For DR BID (500 or 1000 mg), poor compliance scenarios included: 1) One dose taken 3 h, 6 h, 9 h, 12 h (missed dose, no make-up dose), 12 h (two doses, dose double-up) late from schedule; and 2) Two doses taken 3 h, 6 h, 9 h, 12 h after 2^nd missed dose. A 1-compartement model; assuming mono-therapy (adults), was used. The % of subjects on ER 1000 QD that had sub therapeutic concentrations (C[sub]u[/sub] [lt]5 mg/l, C[sub]tot[/sub][lt]50 mg/l) varied from (43-100%, C[sub]u[/sub]) and from (28-100%, C[sub]tot[/sub]). None of the subjects on ER 2500 QD had sub therapeutic concentrations when one dose is taken 12 h late but [sim] 50% of the population had sub therapeutic levels if one dose is missed; while all subjects were sub therapeutic if two doses are missed. Potential toxicity (C[sub]tot[/sub][gt]150 mg/l) may occur in 52% of the population if two doses are taken 18 h after the 2^nd missed dose. While on DR 500 BID, (3-88 %, C[sub]u[/sub]) and (3-77%, C[sub]tot[/sub]) of the population had sub therapeutic levels. For DR 1000 BID, none of the subjects experienced sub therapeutic concentrations if one dose is missed. However, if two doses (DR 1000) are delayed from schedule, 1-24 % (C[sub]u[/sub], C[sub]tot[/sub]) of the population might have sub therapeutic concentrations. While on DR, Replacement doses didn[rsquo]t result in C[sub]tot[/sub] [gt]150 mg/l. Since C[sub]tot[/sub]^VPA show higher inter-individual variability and can under-estimate the effect of poor compliance, The use of C[sub]u[/sub]^VPA for monitoring may be more useful. Patients on ER 1000 QD and DR 500 BID should replace missed doses as soon as remembered. Patients on DR 1000 BID may not need to replace one missed dose but should replace two missed doses as soon as possible, with no risk of toxicity. Patients on ER 2500 should replace missed doses up to 12 h late. Doubling the dose is not advised. Replacing two ER 2500 doses might result in toxicity. (Supported by Abbott Labs)