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 (C(max)) was achieved approximately 4 hours after dosing. VPA absorption was complete ( approximately 93% of dose) within 3 absorption half-lives ( approximately 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 C(max). 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: 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.