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NEUROLOGY

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

Associate Director and Associate Research Fellow, Clinical Pharmacokinetics, Abbott Laboratories, Abbott Park, IL

Ronald C Reed, PharmD

Senior Clinical Research Scientist, Neuroscience Global Pharmaceutical Research & Development, Abbott Laboratories

Robert F O'Dea, PhD MD

Director of Clinical Research, Medical Affairs, Abbott Laboratories

Reprints: Dr. Dutta, Abbott Laboratories, Dept. R4PK, Bldg. AP13A, 100 Abbott Park Rd., Abbott Park, IL 60064-6104, fax 847/938-5193, Sandeep.Dutta{at}abbott.com

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 (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 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.

Key Words: absorption, pharmacokinetics, valproate, valproic acid: controlled release, delayed release, extended release, sustained release

Published Online, March 28, 2006. www.theannals.com, DOI 10.1345/aph.1G617