Effect of delayed and/or missed enteric-coated divalproex doses on valproic acid concentrations: simulation and dose replacement recommendations for the clinician1

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Background and objective

Enteric-coated, delayed-release divalproex sodium requires multiple daily administrations and high adherence rate to prevent breakthrough seizures and control adverse effects. We evaluated the effect of missing one or two doses of divalproex for up to 24 h, followed by replacement and resumption of scheduled therapy, on plasma valproic acid (VPA) concentrations.


Comprehensive simulations using well-established VPA pharmacokinetic parameters were performed for two distinct populations on every-12-h divalproex therapy: monotherapy patients and polytherapy patients on hepatic enzyme-inducing antiepileptics.


In polytherapy patients on c. 32·1 mg/kg/day, steady-state (no missed doses) mean VPA minimum (Cmin) and maximum (Cmax) concentrations were 67 and 98 mg/L, respectively. When dose(s) were missed for 12, 18 and 24 h, mean Cmin fell to 37, 28 and 20 mg/L, respectively, below the threshold 50 mg/L VPA concentration generally required to maintain efficacy. Replacing, then resuming the next regularly scheduled divalproex dose increased mean Cmax to 113, 117 and 129 mg/L upon replacement at 12, 18 and 24 h, respectively; a mean increment of 31 mg/L for replacement at 24 h. Less pronounced changes in VPA concentrations occurred in monotherapy patients (enzyme-uninduced) on ∼16·1 mg/kg/day.


These simulations predict that the risk of high VPA concentrations which may lead to clinical toxicity is low for patients not concurrently taking enzyme-inducing antiepileptic drugs (uninduced), even when divalproex doses are replaced at 24 h(effectively tripling the dose at that time). However, the same action in induced patients may result in drug levels leading to transient clinical toxicity; the optimal regimen for replacing a missed enteric-coated divalproex dose beyond 12 h remains to be determined.

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