What Is the Best Strategy for Converting from Twice-Daily Divalproex to a Once-Daily Divalproex ER Regimen?

Ronald C. Reed; Sandeep Dutta


Clin Drug Invest. 2004;24(9) 

In This Article

Abstract and Introduction

Objective: To examine if, during conversion from conventional divalproex to once-daily divalproex extended-release (ER) tablets, plasma valproic acid (VPA) concentrations in the first 48 hours after conversion are maintained within the accepted therapeutic range (50-100 mg/L).
Methods: Four distinct 12-hourly (q12h) divalproex to once-daily divalproex ER conversion strategies were explored: immediate, delayed, stepwise and mixed conversion. These strategies were each used in simulations for hypothetical adult patients being treated under different conditions: monotherapy (uninduced, at 1500 mg/day divalproex ER) and polytherapy on enzyme-inducing co-medications (induced, at 3000 and 4500 mg/day divalproex ER).
Results: The proportion of uninduced patients expected to have minimum VPA concentrations (Cmin) >50 mg/L was 90% for immediate, 83% for stepwise and 82% for mixed-conversion strategies; only 52% undergoing a delayed-conversion strategy had Cmin >50 mg/L. More importantly, 33% of induced patients under-going delayed conversion to 3000 mg/day divalproex ER maintained an adequate VPA Cmin. Maximum VPA concentrations (Cmax) attained after conversion to divalproex ER are unlikely to rise beyond the steady-state Cmax observed with divalproex q12h regimens with any conversion strategy tested in uninduced or induced patients. Marked perturbation in VPA concentration is not likely when converting to once-daily divalproex ER 'all-at-once' 12 hours after the last divalproex q12h dose. Stepwise and mixed-conversion strategies do not offer any advantage; delayed conversion may produce a large drop in VPA concentration.
Conclusions: An ideal conversion strategy for q12h divalproex to once-daily divalproex ER appears to be an immediate conversion 12 hours after the last divalproex q12h dose; it causes the least perturbation in plasma VPA, even for patients required to take high divalproex ER doses.

Conventional enteric-coated, delayed-release divalproex sodium tablets (Depakote®, Abbott Laboratories, Abbott Park, IL, USA) are routinely used in various epilepsy disorders[1,2] and for prophylaxis of migraine headache,[3,4] as well as for treatment of mania associated with bipolar disorder.[5] Because of the short elimination half-life of valproic acid (VPA) [10-16 hours],[6,7,8] the conventional enteric-coated divalproex tablet is generally administered several times a day. Additionally, several commonly used antiepileptic drugs (AEDs), such as carbamazepine, phenytoin, phenobarbital and primidone, are hepatic enzyme inducers.[9] In patients with epilepsy receiving these enzyme-inducing co-medications, VPA elimination is significantly enhanced (clearance is approximately doubled) and elimination half-life shorter (6-10 hours) compared with values in enzyme-uninduced patients receiving VPA monotherapy.[6,7,8]

Once-daily administration of medication has been shown to substantially enhance patient compliance compared with more frequent administration.[10,11] A new extended-release (ER) tablet formulation of divalproex sodium (Depakote ER®, Abbott Laboratories, Abbott Park, IL, USA) has been approved for once-daily administration in patients with migraine headache[12,13] and epilepsy.[13,14,15,16,17] This once-daily divalproex ER formulation is unique: VPA absorption occurs at a constant, slow rate, without evidence of premature release of medication contents from the tablet (no 'dose dumping') in healthy individuals and enzyme-induced patients with epilepsy, producing a flat plasma VPA concentration-time curve over the entire 24-hour dosing interval;[16,17,18] and the degree of fluctuation in plasma VPA concentrations is significantly reduced.[15,16,17]

A myth exists that 'tinkering or tweaking' of the divalproex ER dose is necessary before conversion of multiple daily doses of conventional divalproex to divalproex ER administered once daily. Some clinicians have been using unconventional and needlessly laborious conversion strategies when switching from conventional multiple daily divalproex to once-daily divalproex ER administration. These dose conversion strategies commonly involve tapering of the multiple daily dose conventional divalproex, giving a portion of the required divalproex ER dose daily incrementally, combinations of these two methods, or merely waiting 24 hours after the last divalproex dose before instituting a once-daily divalproex ER regimen. Since the usually accepted therapeutic window for plasma total VPA concentrations is 50-100 mg/L,[6,7,8] clinicians may be motivated to employ various unconventional conversion strategies because of the potential for clinically significant perturbations in plasma VPA concentrations. There is a perception that perturbations such as a marked fall in plasma VPA concentrations below 50 mg/L with subsequent breakthrough symptoms, or clinical toxicity upon immediate introduction of the divalproex ER dose, with VPA concentrations substantially greater than 100 mg/L, may occur in the first 48 hours of divalproex to divalproex ER conversion unless such tinkering or tweaking of the dose or timing of the dose is performed.

Computer simulation is the most appropriate tool to identify the likelihood of potentially clinically significant perturbations in plasma VPA concentrations upon conversion to once-daily divalproex ER. Attempting to study the impact of potential fluctuations in plasma VPA concentrations upon various conversion strategies of divalproex to once-daily divalproex ER in patients would be very difficult in actual patients in a prospective fashion; it would be expensive, time-consuming and unethical (some strategies could place the patient at risk due to potential breakthrough symptoms or clinical toxicity).

The objectives of this computer simulation experiment were 2-fold. First, to analyse potential perturbations that occur in steady-state plasma total VPA concentrations within the first 48 hours upon converting an adult patient from conventional divalproex administered every 12 hours (q12h) to a proportional dose of divalproex ER given once daily under several different conversion strategies and different patient conditions (treatment with divalproex monotherapy [uninduced] and treatment with divalproex plus concomitant enzyme-inducing anti-epileptic drugs [induced]). Second, to provide practical recommendations to clinicians for the best strategy for converting from a divalproex q12h regimen to a proportional once-daily divalproex ER regimen.