Predicted serum valproic acid concentrations in patients missing and replacing a dose of extended-release divalproex sodium

Abstract

Computer simulations were used to analyze changes in steady-state total plasma valproic acid concentrations when a patient misses a dose of once-daily extended-release divalproex sodium, replaces it at a later time, and resumes scheduled therapy. Valproic acid concentration-time profiles were simulated for 1000 hypothetical patients for each of two missed-dose scenarios using a one-compartment (assumes rapid distribution) population kinetic model with nonlinear protein binding. For each scenario, a lognormal distribution of clearance of unbound valproic acid, volume of distribution of unbound valproic acid, protein-binding values, and albumin concentration was generated. All simulations incorporated 20% interpatient variability and 10% residual error. Our pharmacokinetic simulations predicted that the chance for high plasma valproic acid concentrations resulting in clinical toxicity is low when extended-release divalproex doses are replaced within 12 hours followed by resumption of scheduled administration, perhaps due to the controlled, near zero-order absorption characteristics of the extended-release formulation. If a patient misses a dose of extended-release divalproex, it should be replaced as soon as the patient remembers. The next dose should be taken at the regularly scheduled time. A missed dose of extended-release divalproex may be replaced up to 12 hours later without any clinically significant change in plasma valproic acid concentrations in a majority of the patients. Simulation of two scenarios suggested that a missed dose of extended-release divalproex sodium may be replaced up to 12 hours later without any clinically significant perturbation in plasma valproic acid concentrations in the majority of adolescent and adult patients with epilepsy.