Abstract
Divalproex sodium extended-release (Depakote ER) is a once daily (QD) formulation for valproic acid that was developed to improve patient compliance and to reduce side effects compared with the standard twice-daily (BID) delayed release (DR) formulation (Depakote tablets). However, there are concerns of potential sub-therapeutic concentrations following delayed or missed doses or toxic concentrations with replacement doses for the ER and DR formulations. Simulations can be used to investigate the effect of poor compliance on drug concentrations, which may not be possible to do in a study population for ethical or practical reasons. Using Monte Carlo simulations, the effect of different patterns of poor compliance on ER QD and DR BID were systematically characterized. Non-linear binding of valproic acid to albumin was incorporated into the model, and the results were based on total and unbound VPA for comparison. The effect of poor compliance is less significant on DR BID compared with ER QD. Dosing recommendations in the case of a missed or delayed dose are both formulation and dose dependent. Since total VPA concentrations show higher inter-individual variability and tend to under-estimate the effect of poor compliance; the use of unbound VPA concentrations may offer an advantage in therapeutic monitoring.
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