MORNING VERSUS EVENING DOSING OF DIVALPROEX EXTENDED-RELEASE TABLETS DOES NOT MAKE A DIFFERENCE: A BIOPHARMACEUTIC AND SAFETY COMPARISON
Abstract number :
1.268
Submission category :
Year :
2003
Submission ID :
3855
Source :
www.aesnet.org
Presentation date :
12/6/2003 12:00:00 AM
Published date :
Dec 1, 2003, 06:00 AM
Authors :
Sandeep Dutta, Ronald C. Reed, Alex H.C. Chun, Yiming Zhang, John H. Cavanaugh Clinical Pharmacokinetics, Abbott Laboratories, Abbott Park, IL; Neuroscience, Abbott Laboratories, Abbott Park, IL; Statistics, Abbott Laboratories, Abbott Park, IL; Clinical
Enteric-coated divalproex sodium (Depakote[reg]) is well known for the treatment of epilepsy. A novel once daily divalproex extended-release (ER) tablet formulation (Depakote[reg] ER) has recently been approved. Informal clinician surveys indicate that night-time daily dosing of divalproex ER, rather than morning daily dosing, is frequently utilized to minimize the potential for adverse effects (AEs). To date, no information exists concerning divalproex ER absorption profiles with nocturnal dosing.
In a two-period, repeat dose, randomized crossover study in 16 healthy subjects, divalproex was given either as twice-daily 500 mg divalproex or as a once-daily 1000 mg divalproex ER in the morning or evening. Valproic acid concentration-time profiles were used to assess pharmacokinetics. Statistical analysis of pharmacokinetic parameters included ANOVAs. Safety was evaluated based on AEs, physical examinations, vital signs, and laboratory assessments.
The time of divalproex ER dosing (i.e., morning vs. evening) had no significant effect on valproic acid bioavailability. All regimens were equivalent. Once-daily divalproex ER significantly (p[lt]0.05) reduced mean peak levels (Cmax) but produced similar mean trough levels (Cmin) compared to the twice-daily divalproex regimen. Mean steady state valproic acid exposure (AUC[sub]0-24[/sub], mgh/L), Cmax (mg/L) and Cmin (mg/L) were 1771, 87.0 and 55.5 for 1000 mg once-daily divalproex ER morning dosing, 1728, 85.0 and 57.4 for 1000 once-daily divalproex ER evening dosing, and 1773, 100 and 54.0 for 500 mg twice-daily divalproex regimens, respectively. AE frequency was similar between divalproex ER and divalproex groups for asthenia (n=4), headache (n=3) and somnolence (n=3). However, gastrointestinal AEs occurred in 2 subjects taking divalproex ER, but in 7 on divalproex. All AEs were mild or moderate; none caused withdrawal from the study. There were no significant differences in the pharmacokinetic parameters (p[gt]0.05) and safety between subjects who received the ER formulation in the morning and those who received the ER formulation in the evening.
The results demonstrate the extended-release characteristics of the divalproex ER formulation. This study indicates that once-daily treatment with divalproex ER, given either in the morning or evening may be a suitable replacement for twice-daily dosing with divalproex.
[Supported by: Abbott Laboratories]