Comparative Absorption Profiles of Divalproex Sodium Delayed-Release Versus Extended-Release Tablets—Clinical Implications

Abstract

Background: The distinct absorption characteristics of the conventional enteric-coated, delayed-release (DR) and the novel extended-release (ER) divalproex sodium formulations are not well recognized. Objective: To quantitatively and qualitatively differentiate the absorption characteristics of divalproex-DR and -ER formulations. Methods: Healthy volunteers (N = 28) received single 1000 mg doses of divalproex-DR and divalproex-ER tablets in a crossover fashion. Noncompartmental and compartmental analyses were used to estimate valproic acid (VPA) pharmacokinetics from the plasma concentration–time profiles determined from intensive blood sampling over 48 hours. Results: VPA was not absorbed from divalproex-DR in the first 2 hours (absorption lag-time) after dosing. After VPA release in the intestine, approximately 63% of the dose was absorbed in less than 1 hour, that is, 2.9 hours (mean absorption time) from dosing. Maximum concentration (Cmax) was achieved approximately 4 hours after dosing. VPA absorption was complete (~93% of dose) within 3 absorption half-lives (~4.5 h) post-absorption lag-time, that is, 6–7 hours from dosing. In contrast, VPA absorption from divalproex-ER starts immediately after administration, initially at a modest rate, followed by slow and extended absorption at a constant rate for more than 20 hours; VPA concentrations at 1 and 2 hours were 28% and 40% of Cmax. Approximately 53% of the dose was absorbed within 12 hours (mean absorption time); complete absorption occurred over more than 20 hours without any dose dumping. Conclusions: When antihypertensive treatment options are clinically equivalent, prescribers may first consider using a verapamil SR–based strategy, especially in patients with CAD who have no history of depression. VPA absorption from enteric-coated divalproex-DR is rapid following a lag-time of approximately 2 hours and is complete within 6–7 hours of dosing. In contrast, VPA absorption from divalproex-ER starts immediately after administration, but occurs at a slow, approximately constant rate over more than 20 hours.