Evaluation of antiseizure medication concentration ranges in blood samples using an automated big data approach

The aim of the study is to provide insight into the real-world use of therapeutic drug monitoring (TDM) for the most common antiseizure medications (ASMs).

In total, 137 586 samples from the period 2019-2023 were collected from the five main Danish laboratories performing TDM. A previously described algorithm developed to exclude abnormal TDM results from patient data was applied. This resulted in the inclusion of 84 951 samples from 53 406 patients. Concentration ranges were calculated as 10th to 90th percentiles for the datasets of the ASMs: brivaracetam, carbamazepine, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, phenobarbital, topiramate, valproic acid, and zonisamide. The observed concentration ranges were compared to the established reference ranges from Danish laboratories, the International League Against Epilepsy (ILAE), and the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP). Furthermore, data were stratified based on sex, age groups (0-17, 18-64, and 65-100 years) and indication (all indications vs psychiatric indication).

The observed concentration ranges showed good overall concordance with reference ranges from Danish laboratories except for levetiracetam, whereas the ranges for brivaracetam, lacosamide, lamotrigine, levetiracetam, valproic acid, and zonisamide were different from the AGNP and ILAE guidelines. Age-related differences were identified for several of the drugs. The calculated range of lamotrigine was lower in samples requested from psychiatric departments compared to samples from non-psychiatric departments.

The applied automated approach can facilitate a fast and efficient method for comparing established reference ranges with nationwide TDM datasets, thereby allowing continual monitoring of laboratory reference ranges. The findings from this study suggest that the Danish reference range for levetiracetam should be reevaluated. Furthermore, dose adjustment may be relevant for levetiracetam, topiramate, and lacosamide to account for age-related changes in metabolism. The lower concentration range for lamotrigine in the psychiatric population indicates that it may be effective at lower concentrations in patients with bipolar disorder compared to patients with epilepsy.