Abstracts

Divalproex extended-release (ER), administered once-daily (QD), 1-5g total daily dose, maintains plasma valproic acid concentrations ([VPA]) 24hrs, vs. multiple-daily dose enteric-coated, delayed-release (DR) divalproex ([italic]Ped Neurol[/italic] [apos]04). Clinically, QD enteric-coated sodium valproate (EC-NaVPA, European, [underline][sim][/underline] but not identical to DR, USA) reduces seizures (sz) ([italic]Acta Neurol Scand[/italic] [apos]84). Yet, those treated with QD EC-NaVPA had 1[ordm] generalized sz, responsive to low VPA doses, [sim]15.6-19.4 mg/kg/day ([italic]Epilepsia[/italic] [apos]79). While low EC-NaVPA or DR doses, given QD, may be therapeutically acceptable and occasionally prescribed, we hypothesize that a QD DR regimen should not be applied to refractory epilepsy (partial [underline]+[/underline] 2[ordm] gen. sz) requiring high total daily doses, e.g. 35.6-56 mg/kg/day ([italic]Neurol [/italic][apos]97), due to the potential for excessively high peak [VPA] ([gt]125mg/L). We examined the impact of QD divalproex dosing, DR [italic]vs[/italic]. ER, on steady-state [VPA] profiles at commonly used doses in monotherapy ([italic]uninduced[/italic], UN) and polytherapy (hepatic enzyme-[italic]induced[/italic], IND) virtual patients., Scenarios include adults with epilepsy, UN/IND; QD DR doses from 1125- 4000mg vs QD ER (mg dose-proportional ER, all scenarios) chronically. [VPA]-time profiles were simulated, each scenario (n=1000) using a 1-compartment population (20% inter- [amp] 10% intra-patient variability) kinetic model with nonlinear protein binding (Monte Carlo stochastic simulations, Clinical Trial Simulator software) ([italic]Am J Health-Sys Pharm[/italic] [apos]04)., Only 1125mg QD DR dose had mean C[sub]max[/sub] [lt]100mg/L (conventional population upper therapeutic VPA range limit); QD DR [underline][gt][/underline]2000mg produced mean C[sub]max[/sub][gt]125mg/L. Mean DR C[sub]min[/sub] was [sim]50mg/L (conventional lower VPA limit) at 2 doses, whereas mean ER C[sub]min[/sub] was [gt]70mg/L at all doses tested. Excursions well beyond the recommended range of 50-100 mg/L are predicted to commonly occur on QD DR, evidenced by 10^th-90^th percentile data (considering 80% of patients, DR C[sub]max[/sub] is frequently [gt]100 mg/L [amp] C[sub]min [/sub][lt]50 mg/L). DR degree of peak-trough fluctuation (DFL) was 4.4x-6.2x [gt] ER.[table1], QD dosing of ER is appropriate over a large range of total mg/day, but not for QD DR [underline][gt][/underline] 2000 mg. QD DR dosing should not be attempted for sz requiring high total daily doses due to potential [VPA] excursions beyond 50-100 mg/L, risking breakthrough sz or toxicity., (Supported by Abbott Labs.)