Divalproex to Divalproex Extended Release Conversion

Sandeep Dutta; Ronald C. Reed


Clin Drug Invest. 2004;24(9) 

In This Article

Conclusions and Clinical Implications

Divalproex ER has lower bioavailability than divalproex (divalproex ER/divalproex AUC ratio approximately 0.89). While switching patients from a divalproex to a divalproex ER regimen, the divalproex ER daily dose may have to be increased by an average of 12% to achieve comparable plasma exposure. Since divalproex ER dosage strengths (250 and 500mg) are not 12% higher than divalproex dosage strengths (125, 250 and 500mg), an 8-20% higher divalproex ER daily dose should be considered for conversion from divalproex to divalproex ER. The effect of food on divalproex ER/divalproex relative bioavailability is minimal. The frequency of the divalproex dose regimen prior to conversion is not expected to affect the divalproex to divalproex ER conversion ratio. The lower fluctuation of VPA concentrations, consistent tmin 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.

The variability in Cmin values is relatively greater than the variability in AUC and Cmax values. Plasma VPA exposure (AUC) and Cmin values are equivalent, on average, when the divalproex ER dose is 8-20% higher than the total daily divalproex dose, but may vary across patients after conversion. The lower Cmax of the divalproex ER formulation may be beneficial to some patients experiencing Cmax-related adverse effects. Comparison of predose concentrations from a divalproex regimen that includes multiple daily administrations with that from a once-daily divalproex ER regimen when converting to divalproex ER has limitations. Therefore, if satisfactory clinical response has not been achieved, plasma VPA concentrations should be measured approximately 24 hours after the last divalproex ER dose to determine whether they are in the recommended therapeutic range (50-100 mg/L).

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