No abstract

Adherence to antiseizure drug treatment determines its effectiveness and safety, and consequently affects patients’ quality of life. Herein, we assessed adherence to levetiracetam in Portuguese patients with refractory epilepsy (n = 115), with resort to a pharmacokinetic drug monitoring approach. The pharmacokinetic parameters of levetiracetam in each patient were determined in steady-state while admitted to the hospital. Then, adherence was assessed by comparing the plasma concentration of the drug observed on the first day of hospitalization with the predicted plasma concentration, considering previously determined pharmacokinetic parameters. The rate of adherence was assessed according to gender, age, diagnosis, and antiseizure drug regimen. Among 115 enrolled patients, 49 (42.6%) were identified as non-adherent, 30 (26.1%) classified as under-consumers, and 19 (16.5%) as over-consumers. A relationship between adherence, daily dose and plasma concentrations was herein reported for the first time. Adherent patients received higher daily doses of levetiracetam [2500 (2000–3000) mg] than non-adherent over-consumers [1500 (1000–2000) mg] and non-adherent under-consumers [2000 (1500–3000) mg]. Higher average steady-state plasma concentrations of levetiracetam were found in non-adherent under-consumers [27.28 (15.33–36.36) mg/L], followed by adherent patients [22.05 (16.62–29.81) mg/L] and non-adherent over-consumers [17.50 (10.69–24.37) mg/L]. This study demonstrates that adherence (or lack thereof) influences the plasma concentrations of levetiracetam in steady-state and its pharmacological effects. Moreover, it emphasizes the importance of educating patients to encourage adherence to therapy. Otherwise, the risk of developing toxic and subtherapeutic concentrations is undeniable, compromising the therapeutic effect and safety of treatment.

Perampanel is a promising antiepileptic drug (AED) for refractory epilepsy treatment due to its innovative mechanism of action. This study aimed to develop a population pharmacokinetic (PopPK) model to be further used in initial dose optimization of perampanel in patients diagnosed with refractory epilepsy. A total of seventy-two plasma concentrations of perampanel obtained from forty-four patients were analyzed through a population pharmacokinetic approach by means of nonlinear mixed effects modeling (NONMEM). A one-compartment model with first-order elimination best described the pharmacokinetic profiles of perampanel. Interpatient variability (IPV) was entered on clearance (CL), while the residual error (RE) was modeled as proportional. The presence of enzyme-inducing AEDs (EIAEDs) and body mass index (BMI) were found as significant covariates for CL and volume of distribution (V), respectively. The mean (relative standard error) estimates for CL and V of the final model were 0.419 L/h (5.56%) and 29.50 (6.41%), respectively. IPV was 30.84% and the proportional RE was 6.44%. Internal validation demonstrated an acceptable predictive performance of the final model. A reliable population pharmacokinetic model was successfully developed, and it is the first enrolling real-life adults diagnosed with refractory epilepsy.