Pharmacokinetic variability during long-term therapeutic drug monitoring of valproate, clobazam, and levetiracetam in patients with Dravet syndrome.

Background The use of therapeutic drug monitoring (TDM) for antiseizure medications (ASMs) may contribute to treatment optimization in individual patients. The present study included patients with Dravet syndrome as they often require close monitoring, owing to polypharmacy with various ASMs. The aim was to use long-term TDM to investigate pharmacokinetic variability of ASMs in these patients. Methods Retrospective data from patients with Dravet syndrome were collected from the TDM database at the Section for Clinical Pharmacology, National Center for Epilepsy in Norway (2008-2018). Concentration/(dose/kg)-ratios (C/D-ratios) were calculated for the ASMs, and the concentration (C/C-ratio) for N-desmethylclobazam. In patients with at least three measurements, the coefficient of variation (CV) for C/D-ratios for intra- and inter-patient variability was calculated. Results Fifty-three patients (30 male patients/23 female patients) between 2 and 50 years of age (mean, 16 years) were included. Pharmacokinetic variability of the total number of measurements of valproate (n=417), clobazam and N-desmethylclobazam (n=328), and levetiracetam (n=238) was determined. Inter-patient variability was more pronounced than intra-patient variability (CVs: valproate, 65% vs. 24%; levetiracetam, 71% vs. 27%; clobazam/N-desmethylclobazam, 47%/77% vs. 35%/55%) (p Conclusion Long-term TDM revealed extensive variability in serum concentrations over time; the variability was lowest for levetiracetam, moderate for valproate, and highest for clobazam. Pharmacokinetic variability and interactions can thus be identified and adjusted to facilitate decision-making to achieve the optimal treatment outcome.