Abstracts

Missing and replacing at a later time [m/r], enteric-coated divalproex [dvp] dose(s) given twice daily compared to m/r once-daily extended-release divalproex [dvp-ER] may have different effects on the ability of these formulations to sustain steady-state total plasma valproate concentrations [VPA]. Computer-simulated changes in [VPA] when a patient m/r their dose(s) of multiple-daily dose dvp were compared to a m/r once-daily dvp-ER dose to determine which formulation is better able to sustain [VPA], and therefore is [ldquo]more protective[rdquo] clinically. Various scenarios include virtual adult epilepsy patients, taking dvp 562.5mg q12h, compared to dvp-ER 1250mg qam (higher dvp-ER dose compensates for lower dvp-ER bioavailability) chronically as monotherapy (uninduced); likewise in polytherapy (hepatic enzyme-induced) patients, taking 1125mg dvp q12h vs 2500mg dvp-ER qam. [VPA] was analyzed when dvp or dvp-ER dose(s) were missed, then replaced at 12, 18 or 24 hours, while resuming scheduled therapy with the next dvp or dvp-ER dose(s) at 24 hrs. [VPA]-time profiles were simulated for 1000 hypothetical patients for each scenario using a 1-compartment population kinetic model with nonlinear protein binding (Monte Carlo stochastic simulations, ADAPT II software) and incorporated 20% inter-patient variability and 10% residual error. In induced patients, steady-state baseline (no m/r dose) mean [VPA] Cmin and Cmax values for dvp were 67 and 98 mg/L, and for dvp-ER were 81 and 88 mg/L, respectively. When dvp dose(s) were m/r, mean [VPA] Cmin values fell to 37, 28 and 20 mg/L upon replacement at 12, 18 and 24 hrs, respectively. Replacing, then resuming dvp increased the mean [VPA] Cmax values to 113, 117 and 129 mg/L upon replacement at 12, 18 and 24 hrs; maximum mean increase of 31 mg/L above the baseline Cmax. When a dvp-ER dose was m/r, mean [VPA] Cmin values fell to 46, 34 and 25 mg/L upon replacement at 12, 18 and 24 hrs, respectively. Replacing, then resuming dvp-ER bumped the mean [VPA] Cmax values up to 107, 111, 114 mg/L upon replacement at 12, 18, 24 hrs; maximum mean increase of only 26 mg/L above the baseline Cmax. For these simulations, %CVs ranged from 22% to 61%. When dvp doses or a dvp-ER dose is m/r at 24 h, 90% of patients would have a [VPA] Cmax increment of [lt]43 or [lt]33 mg/L, for dvp or dvp-ER, respectively. In uninduced patients, [VPA] changes were similar, but less pronounced. The fall in [VPA] after missing the dvp or dvp-ER dose(s) is pronounced in the induced patient, especially at 24 hours; replacing the missed dvp or dvp-ER dose(s) while resuming therapy produces a large, but not unexpected rise in [VPA]. Our simulations predict multiple-daily dvp is not more protective than daily dvp-ER in the case of m/r dose(s) with respect to maintenance of [VPA]. (Supported by Abbott Laboratories)