Divalproex to Divalproex Extended Release Conversion

Sandeep Dutta; Ronald C. Reed


Clin Drug Invest. 2004;24(9) 

In This Article

Valproic Acid t

The time to Cmax (tmax) and Cmin (tmin) values determined following administration of divalproex or divalproex ER are summarised in Table II . The steady-state tmax and tmin values were calculated over one dosing interval for divalproex ER regimens, i.e. 24 hours. For comparison with the divalproex ER regimen, the tmax and tmin values for the reference divalproex regimens were also calculated over 24 hours, i.e. over two, three or four dosing intervals.

The median tmax values for the divalproex ER once-daily regimens ranged from 4.0 to 16.5 hours across the various studies and food conditions. The large variability in the median tmax values for divalproex ER is not surprising, as this product, like other extended-release products, was designed to produce a smoother concentration-time profile, i.e. with less peak-trough fluctuation, when compared with conventional products (e.g. divalproex). However, the median tmin values for divalproex ER once-daily regimens were, as expected, less variable and consistently around 24 hours.

The median tmax values for the divalproex regimens ranged from 3.0 to 15.0 hours and the median tmin values ranged from 6.0 to 19.5 hours across the various studies and food conditions. The tmax and tmin values for the divalproex regimens that are administered more than once daily are more difficult to interpret; several factors are involved, as discussed in the following paragraphs.

For therapeutic drug monitoring of most drugs, often trough (i.e. predose) concentrations are monitored. In general, this is assumed to be the minimum concentration that is likely to occur during a dosing interval. This is not necessarily true and is more doubtful for dosage forms that are administered more than once daily. Therefore, several factors should be taken into consideration during evaluation of trough concentrations when converting from a dosage form that is administered multiple times daily to once-daily dosage forms.

It should be recognised that Cmin and Ctrough values could be substantially different for conventional divalproex tablet regimens. This is illustrated by data from studies 2, 3, 4 and 5 presented in Figure 1 and from the tmin values presented in Table II . For divalproex regimens that consist of multiple administrations during a day, several factors can affect the tmin during a 24-hour period. First, there may be two (q12h), three (q8h) or four (q6h) possible predose concentrations during a 24-hour period depending on the divalproex dosing frequency. Second, the administration of divalproex tablet, which is enteric coated to resist dissolution in the acidic gastric environment, is associated with a lag time before the drug is released from the tablet.[18] During multiple dosing, VPA concentrations decline for the first few hours (i.e. lag time) after each dose administration because significant absorption from the most recent dose does not occur during this lag time.[18] Third, this lag time is usually 1-4 hours when the drug is administered under fasting conditions and usually 2-8 hours when administered with food.[18] As a result, during a dosing interval within a day, the Cmin may actually occur 1-8 hours after administration depending on the lag time and whether the dose was taken with food. Fourth, there is substantial evidence of diurnal variation in VPA concentrations.[5,6,7,8,9,10] Fifth, for divalproex regimens where the total daily dose cannot be equally divided during a day, a patient's dose will not be the same for all times of the day. This can also affect tmin values over a 24-hour period. Sixth, in a real-world situation, the divalproex doses are more likely to be taken under the less rigorous unequal dosing intervals of four-times-daily, three-times-daily or twice-daily regimens rather than the equal dosing interval q6h, q8h or q12h regimens of the bioavailability studies. This unequal administration frequency will increase the variability in tmin. Seventh, as adherence often decreases with increasing dose frequency,[3] poor adherence associated with higher frequency of divalproex regimens is more likely to affect the Cmin and tmin values of the divalproex regimens, compared with the expected higher adherence to the once-daily divalproex ER regimen. Therefore, during a 24-hour period, the tmin for divalproex regimens is more variable and depends on the frequency of administration, lag time, effect of food, diurnal variation, dose and dosing interval for each individual administration and adherence.

Divalproex ER is a matrix dosage form that is designed to release drug at a constant, apparent zero-order rate over 18-22 hours.[19] Therefore, as shown in Table II for divalproex ER once-daily regimens, the Cmin generally occurs about 24 hours after drug administration, i.e. Cmin and Ctrough values are identical or similar. As pretreatment trough level for the divalproex ER regimen is a more reliable indicator of minimum plasma VPA value during a 24-hour dosing interval, divalproex ER has some distinct advantages over divalproex with respect to dose titration and therapeutic drug monitoring when a single plasma VPA concentration from a dosing interval is used for monitoring.

Simple comparison of predose concentrations from a divalproex regimen with those from a divalproex ER regimen when converting to divalproex ER may not reflect the true ratio of Cmin values. The observed divalproex ER/divalproex Cmin ratio may be biased, as the true Cmin value is less likely to be captured for the divalproex regimen. Therefore, as the tmin for divalproex regimens depends on several factors, including the frequency of administration, lag time, effect of food, diurnal variation, dose and dosing interval for each individual administration and adherence, providing succinct guidance to the clinician regarding therapeutic drug monitoring based on comparison of Ctrough values while converting from divalproex to divalproex ER has limitations. Although providing clear and concise guidance regarding therapeutic drug monitoring during divalproex to divalproex ER conversion is difficult, once a patient has been converted to once-daily divalproex ER, therapeutic monitoring should be optimally based on Ctrough values determined from plasma samples collected approximately 24 hours after the last divalproex ER dose. Clinicians should continue to follow the established guidance of maintaining plasma VPA concentrations in the recommended therapeutic range (50-100 mg/L).