Pharmacokinetics and safety of extended-release divalproex sodium tablets: morning versus evening administration.
Author(s): Dutta S, Reed RC, Cavanaugh JH
Affiliation(s): Clinical Pharmacokinetics Abbott Laboratories, Abbott Park, IL 60064-6104, USA. firstname.lastname@example.org
Publication date & source: 2004-11-01, Am J Health Syst Pharm., 61(21):2280-3.
Publication type: Clinical Trial; Randomized Controlled Trial
PURPOSE: The pharmacokinetics and safety of 1000-mg extended-release divalproex sodium given once daily either in the morning or evening were compared. METHODS: Healthy volunteers 19-55 years of age were enrolled in this open-label, parallel-design study. Subjects were randomized to receive extended-release divalproex either in the morning or in the evening. Blood samples were taken immediately before and at 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 121, 122, 123, 124.5, 126, 127.5, 129, 130.5, 132, 133, 134, 135, 136.5, 138, 139.5, 141, 142.5, and 144 hours after the first dose of each six-day regimen. Plasma samples were assayed for total valproic acid concentrations using gas chromatography. Valproic acid pharmacokinetic values were measured, and the safety of each regimen was evaluated. RESULTS: Mean steady-state valproic acid exposure, maximum concentration, and minimum concentration were 1771 mg x hr/L, 86.9 mg/L, and 55.5 mg/L for the morning dosing and 1728 mg x hr/L, 84.8 mg/L, and 57.4 mg/L for the evening dosing regimens, respectively. Adverse events reported by two or more subjects were abdominal pain and somnolence for the morning dosing regimen and asthenia, headache, and pain for the evening dosing regimen. All adverse events were mild or moderate; none caused subject withdrawal from the study. There were no significant differences in the pharmacokinetic parameters (p > 0.51) and safety between groups. Diurnal variation in plasma valproic acid concentrations was minimal with once-daily administration of extended-release divalproex. CONCLUSION: Evening once-daily administration of extended-release divalproex was not associated with substantial differences in pharmacokinetics or safety compared with morning once-daily administration.