Abstracts

Twice daily dosing with conventional divalproex (Depakote[reg], dvpx), is well known for the treatment of headache and epilepsy. Once daily dosing with a novel dvpx extended-release tablet (Depakote[reg] ER) has been approved. Conversion from dvpx to once daily dosing with dvpx ER may enhance compliance. However, some clinicians have been using unconventional, and needlessly laborious conversion strategies, involving tapering of dvpx combined with stepwise increases in ER doses. Clinicians are concerned that perturbations in steady-state plasma valproate concentrations [VPA] may occur in the first 12 to 24 hr post-conversion. This was examined via computer simulation for different patient scenarios. Practical recommendations for appropriate timing and doses for conversion are made.
Two scenarios include: 1) adult patients on VPA monotherapy taking 625 mg dvpx q12h chronically (baseline); converting to 1500 mg once daily AM or PM ER dose 12 or 24 hr after the last dvpx dose; 2) adult patients on enzyme-inducing AEDs, taking 2000 mg dvpx q12h at steady-state, followed by conversion to 4500 mg once daily AM or PM ER dose, 12 or 24 hr after the last dvpx dose. Other conversion strategies, such as using a dvpx dose in the AM, then half ER dose in the PM, or half the ER dose both in the AM and PM, prior to converting to once daily ER, were also explored. Adjusted ER doses utilized for converting from dvpx were based on a published dosing strategy for providing equivalent exposure (Dutta et al, Epil Res 2002;49:1-10). [VPA]-time profiles were simulated for 1000 hypothetical patients using a 1-compartment population kinetic model with nonlinear protein binding (Pharsight[reg] Trial Simulator). Simulations incorporated 20% inter- and 10% intrasubject variability.
For both hypothetical patient scenarios, the immediate, [ldquo]all at once[rdquo] conversion from q12h dvpx dosing to the appropriate daily ER dose 12 hr later produces a smooth [VPA] time curve. As expected, [VPA] C[sub]max[/sub] is reduced, C[sub]min[/sub] is slightly increased and C[sub]avg[/sub] is similar. For patients who change 12 hr after the last dvpx dose, 88% of monotherapy and 96% of polytherapy patients are expected to have C[sub]min[/sub] values [gt]50 mg/L. However, as expected for a conventional formulation designed to provide coverage for only 12 hr, each scenario shows that waiting 24 hr to convert dvpx to ER produces marked, potentially clinically significant falls in plasma [VPA]; only 50% of monotherapy and 58% of polytherapy patients had C[sub]min[/sub] [gt]50 mg/L at doses listed.
These simulations suggest that no significant perturbation in plasma [VPA] is likely when converting dvpx q12h to daily ER [ldquo]all at once[rdquo] 12 hr after the AM or PM dvpx dose. Waiting 24 hr to convert from dvpx to ER results in too large a drop in plasma [VPA] and is not recommended. For daily ER dosing, there is no apparent advantage in converting dvpx to ER in small steps; no tapering of dvpx with concurrent ER upward dose titration is needed.
[Supported by: Abbott Laboratories.]