Divalproex to Divalproex Extended Release Conversion

Sandeep Dutta; Ronald C. Reed


Clin Drug Invest. 2004;24(9) 

In This Article

Abstract and Introduction

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.

Divalproex sodium extended release (ER) tablet (Depakote® ER, Abbott Laboratories, USA, henceforth referred to as divalproex ER) is a novel extended-release formulation of conventional enteric-coated divalproex sodium delayed-release tablets (Depakote®, Abbott Laboratories, USA, henceforth referred to as divalproex). Divalproex is indicated for treatment of seizures, acute manic episodes associated with bipolar disorder and prophylaxis of migraine headaches.[1] Divalproex ER has been approved for prophylaxis of migraine headaches (August 2000) and the treatment of seizures (December 2002) in the US.[2]

Several factors may prompt switching a patient from the enteric-coated divalproex to the once-daily divalproex ER formulation. Patient convenience and acceptance of once-daily formulations is usually higher than for multiple-daily-dose formulations, particularly for children and adolescent patients and their parents. Patient adherence is usually higher with once-daily than with multiple-daily administration, predominantly for patients for whom adherence is an issue or for patients on three- or four-times-daily divalproex regimens (e.g. patients with high elimination clearance because of several concomitant hepatic enzyme-inducing antiepileptic medications).[3] Although not yet conclusively established for valproate therapy, for once-daily formulations that have lower maximum concentrations than conventional formulations, the potential exists for lower peak concentration-related side effects (not all side effects have a direct relationship with peak concentration) with the once-daily formulation.[4] Lastly, plasma valproic acid (VPA) concentrations exhibit diurnal variation due to intrinsic (e.g. gastric emptying rate, free fatty acid levels) and extrinsic (e.g. food, formulation, frequency of administration [one, two, three or four times daily], adherence) factors that complicate therapeutic drug monitoring.[5,6,7,8,9,10] Once-daily divalproex ER administration may produce consistent trough VPA concentrations (Ctrough) that may permit easier therapeutic drug monitoring.

Traditionally, conversion from a formulation that is taken several times a day (e.g. divalproex) to a once-daily extended-release formulation of any therapeutic entity is implemented without any change in the total daily dose. Therefore, during the development of the once-daily divalproex ER formulation, initially three bioavailability studies (two studies in healthy volunteers and one in patients with epilepsy)[11,12,13] compared equal total daily doses of divalproex ER and divalproex. These three studies indicated that the divalproex ER formulation has approximately 11% lower bioavailability than the divalproex formulation. These studies used different divalproex dosing frequencies (every 6 hours [q6h] or every 12 hours [q12h]) and meal conditions (fasting and low-, medium- and high-calorie meals). Divalproex ER was given once daily in all studies.

The key question was whether divalproex ER can be substituted for divalproex in epilepsy safely while maintaining efficacy via pharmacokinetic proof of equivalency in exposure (area under the plasma concentration-time curve [AUC]). Although the concentration-effect (i.e. seizure control) relationship of VPA has not been conclusively established, the usually accepted therapeutic window for plasma total VPA concentrations is 50-100 mg/L.[14] Therefore, it was assumed that achieving equivalent AUC between divalproex ER and divalproex formulations, while achieving equal or higher divalproex ER minimum plasma total VPA concentrations (Cmin) and equal or lower divalproex ER maximum plasma total VPA concentrations (Cmax) compared with corresponding divalproex Cmin and Cmax values, would accomplish this objective. Accordingly, it was predicted that a 12% higher divalproex ER dose (calculated as 1.0/relative bioavailability = 1.0/0.89 = 1.12) would result in an AUC central value that would be equal to the AUC central value of a corresponding divalproex dosage regimen.

The available dosage strengths for divalproex ER (250 and 500mg) were not 12% higher than the marketed divalproex tablets (125, 250 and 500mg). Consequently, two studies, one each in healthy volunteers and patients with epilepsy, compared the bioavailability of 8-20% higher once-daily divalproex ER doses with corresponding total daily divalproex doses.[15,16]