Handling Delayed or Missed Dose of Antiseizure Medications: A Model-Informed Individual Remedial Dosing.

BACKGROUND AND OBJECTIVES: Delayed or missed antiseizure medications (ASMs) doses are common during long-term or lifelong antiepilepsy treatment. This study aims to explore optimal individualized remedial dosing regimens for delayed or missed doses of 11 commonly used ASMs. METHODS: To explore remedial dosing regimens, Monte Carlo simulation was used based on previously identified and published population pharmacokinetic models. Six remedial strategies for delayed or missed doses were investigated. The deviation time outside the individual therapeutic range was used to evaluate each remedial regimen. The influences of patients' demographics, concomitant medication, and scheduled dosing intervals on remedial regimens were assessed. RxODE and Shiny in R were used to perform Monte Carlo simulation and recommend individual remedial regimens. RESULTS: The recommended remedial regimens were highly correlated with delayed time, scheduled dosing interval, and half-life of the ASM. Moreover, the optimal remedial regimens for pediatric and adult patients were different. The renal function, along with concomitant medication that affects the clearance of the ASM, may also influence the remedial regimens. A web-based dashboard was developed to provide individualized remedial regimens for the delayed or missed dose, and a user-defined module with all parameters that could be defined flexibly by the user was also built. DISCUSSION: Monte Carlo simulation based on population pharmacokinetic models may provide a rational approach to propose remedial regimens for delayed or missed doses of ASMs in pediatric and adult patients with epilepsy.

How to handle the delayed or missed dose of rivaroxaban in patients with non-valvular atrial fibrillation: model-informed remedial dosing.

BACKGROUND: Rivaroxaban is an oral anticoagulant widely used for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). During long-term anticoagulant therapy, delayed or missed doses are common. This study aimed to explore appropriate remedial dosing regimens for non-adherent rivaroxaban-treated patients. METHODS: Monte Carlo simulation based on a previously established rivaroxaban population pharmacokinetic/pharmacodynamic (PK/PD) model for patients with NVAF was employed to design remedial dosing regimens. The proposed regimens were compared with remedial strategies in the European Heart Rhythm Association (EHRA) guide by assessing deviation time in terms of drug concentration, factor Xa activity, and prothrombin time. RESULTS: The proposed remedial dosing regimens were dependent on delay duration. The missed dose should be taken immediately when the delay does not exceed 6 h; a half dose is advisable when the delay is between 6 and 20 h. A missed dose should be skipped if less than 4 h remains before the next dose. The proposed regimens resulted in shorter deviation time than that of the EHRA guide. CONCLUSION: PK/PD modeling and simulation provide valid evidence on the remedial dosing regimen of rivaroxaban, which could help to minimize the risk of bleeding and thromboembolism.