Remedial dosing recommendations for valproic acid in nonadherence patients with epilepsy

摘要: Objective: This study investigated the effect of delayed or missed doses on the pharmacokinetics (PK) of valproic acid (VPA) in patients with epilepsy and established remedial dosing recommendations for nonadherence patients. Methods: The Monte Carlo simulations based on all previous population pharmacokinetic models for pediatric, adult and elder patients with epilepsy receiving valproic acid, which is the most commonly used first-line AED. The following three remedial approaches were investigated for each delayed dose: A) A partial dose was administered immediately, and the regular dose was administered at the next scheduled time. B) The delayed dose was administered immediately, followed by a partial dose at the next scheduled time. C) The delayed and partial doses were coadministered immediately, the next scheduled dose was skipped, and the regular dosing was resumed at the subsequent scheduled time. Results: The most appropriate remedial regimen was that with the shortest deviation time from the therapeutic window. The effect of nonadherence on PK was dependent on the delay duration and daily dose, and the recommended remedial dose was related to the delay duration and concomitant antiepileptic drugs. Remedial dosing strategies A and B were almost equivalent, whereas C showed a larger PK deviation time. If one dose was missed, double doses were not recommended for the next scheduled time. Significance: Simulations provide quantitative insight into the remedial regimens for nonadherence patients and clinicians should select the optimal regimen based on the status of patients