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Delayed or missed doses are unavoidable in the pharmacotherapy of epilepsy and significantly compromise the efficacy of antiepileptic drug treatment. An inappropriate remedial regimen can cause seizure relapse or serious adverse events. 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 nonadherent patients. Monte Carlo simulations are based on all previous population pharmacokinetic models for pediatric, adult and elderly patients with epilepsy. The following four remedial strategies were investigated for each delayed dose: A) A partial dose or a regular dose is taken immediately; a regular dose is taken 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 dose and a partial dose are taken; the next scheduled time is skipped, and the regular regimen is resumed. D) Double doses are taken when missed one dose or two doses, and the regular regimen at the subsequent scheduled time is resumed. The recommended remedial dose was related to the delay duration and daily dose. Remedial dosing strategies A and B were almost equivalent, whereas Strategy C was recommended when the delayed dose was close to the next scheduled dose. Strategy D was only suggested for delayed two doses. Simulations provide quantitative insight into the remedial regimens for nonadherent patients, and clinicians should select the optimal regimen for each patient based on the individual's status. Unlabelled Image • Monte Carlo simulation based on population pharmacokinetics is used in the development of remedial dosing recommendation. • Optimal remedial regimen is mainly related to delay duration and daily dose. • Four remedial approaches are proposed and clinicians could select the regimen according to the patient status. [ABSTRACT FROM AUTHOR]

This study investigated the effect of delayed or missed doses on the pharmacokinetics (PK) of lamotrigine (LTG) in children with epilepsy and established remedial dosing recommendations for nonadherent patients. The Monte Carlo simulation based on a published LTG population PK model was used to assess the effect of different scenarios of nonadherence and the subsequently administered remedial regimens. 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. The most appropriate remedial regimen was that with the shortest deviation time from the individual 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. Simulations provide quantitative insight into the remedial regimens for nonadherent patients, and clinicians should select the optimal regimen based on the status of patients. Three remedial strategies identified for a 12-year-old and 40-kg patient administered lamotrigine on 125 mg q12h regimen without an inducer or inhibitor when dose was delayed by 10 h. The dark pink shadow represents the distribution of the 5th–95th percentiles of the simulated concentrations in 90% of the virtual subjects, and the light pink shadows represent the distribution of the simulated concentrations outside the 5th–95th percentiles in the remaining 10% virtual subjects. Red solid line represents median of the simulated concentrations and dotted lines represent 0.5th and 99.5th percentiles of the simulated concentrations, respectively. Black dotted lines represent the individual therapeutic range (2.4–16.8 mg/L). Black solid line represents the deviation time. Unlabelled Image • Monte Carlo simulation was used to develop remedial regimens of nonadherence. • The remedial regimens were dependent on the delayed time and comedications. • Clinicians could select the optimal remedial strategy for individual patients. [ABSTRACT FROM AUTHOR]