Divalproex to divalproex extended release conversion

Abstract

Objective: Divalproex extended release (ER) tablets have lower bioavailability than conventional divalproex tablets. Objectives were to provide dose-increment justification for conversion of a patient from conventional enteric-coated divalproex to a once-daily divalproex ER regimen and to discuss the pharmacokinetic factors affecting these unequal total daily dose conversions.

Methods: Three bioavailability studies (two in healthy volunteers and one in epilepsy patients; total n = 69) compared equal total daily doses, and two studies (one each in healthy volunteers and epilepsy patients; total n = 99) compared 8-20% higher divalproex ER daily doses with corresponding divalproex total daily doses. In all five studies, multiple doses were administered over 6-14 days in each regimen.

Results: For equal total daily dose comparisons, the divalproex ER/divalproex bioavailability (area under the concentration-time curve [AUC] ratio) was ~0.89 and when the divalproex ER dose was higher, the two regimens were equivalent (AUC ratio ~1.0). Divalproex ER administered once daily had less fluctuation in valproic acid concentrations, i.e. divalproex ER achieved equal or significantly higher minimum concentrations and significantly lower maximum concentrations compared with divalproex administered multiple times daily. Divalproex ER predose trough concentration consistently represented the lowest concentration during a dosing interval, whereas for divalproex this was not true because of absorption lag time (from enteric coating), diurnal variation and multiple doses during a 24-hour interval.

Conclusions: An 8-20% higher divalproex ER daily dose should be used when converting from a total daily dose of divalproex. The lower fluctuation of valproic acid concentrations, consistent time to trough concentration, and lower dosing frequency of divalproex ER should offer benefit to the patient by providing convenient once-daily administration, and to the clinician by facilitating easier and reliable therapeutic drug monitoring and improving patient adherence.