Bayesian-Based Pharmacokinetic Framework Integrated with Therapeutic Drug Monitoring for Assessing Adherence to...

Adherence to antiseizure medications (ASMs) is a cornerstone of effective epilepsy management. However, current consensus guidelines for assessing medication adherence via therapeutic drug monitoring (TDM) may neglect individual patient characteristics, thereby compromising the accuracy of adherence assessments.

This study proposed an innovative Bayesian-based pharmacokinetic (PK) framework integrated with TDM data to address the above limitations, with a focus on 14 widely prescribed ASMs, including brivaracetam, carbamazepine, clobazam, eslicarbazepine acetate, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, phenobarbital, topiramate, valproic acid, vigabatrin, and zonisamide.

Comprehensive clinical trial simulations were conducted to investigate the PK of ASMs in patients with epilepsy under conditions of full adherence and various nonadherent dosing behaviors, including omission of the last dose and consecutive missed doses. Bayesian posterior probabilities of these dosing behaviors were derived by integrating validated population PK models, individual patient demographics (eg, age, weight, creatinine clearance), dosing history, prior adherence probabilities and TDM measurements. Additionally, the influence of covariates on assessment outcomes was systematically evaluated.

The Bayesian-based PK approach demonstrated robust discriminative ability. Under idealized simulation conditions with minimized variabilities, the approach achieved accurate retrodiction of the last 1 or 2 doses across all 14 ASMs and partial retrodiction of extended nonadherence trajectories for 6 ASMs. Concentration thresholds for adherence classification varied significantly across drugs and are influenced by patient-specific factors, comedications, formulation, sampling time, and prior probability. To translate these insights into practice, an adaptable web-based dashboard was developed using the shiny package in R software to enable precise and real-time assessments of medication adherence.

This study establishes a Bayesian-based PK approach to enhance the assessment of ASMs adherence. This approach facilitates a paradigm shift from population-based management to patient-specific adherence profiling, offering a practical methodology for the precise evaluation of medication-taking behaviors.