Development and Validation of Linear Regression Models to Predict Plasma-Free Perampanel Concentrations Using Routine Clinical Data

Background: Therapeutic drug monitoring of perampanel, a highly protein-bound antiseizure medication, is typically based on total plasma concentration (Cpt); however, free drug concentrations are more directly associated with pharmacological effects. Measurement of free perampanel concentration (Cpf) is analytically complex and not routinely feasible in clinical practice. This study aimed to develop a practical approach for estimating Cpf using routinely available clinical data. Methods: In this single-center, prospective, observational study, clinically stable adults receiving perampanel for ≥5 days were enrolled, including ambulatory outpatients (n = 17) and hospitalized patients. Cpf and Cpt were quantified using a validated liquid chromatography–tandem mass spectrometry method, with Cpf being measured after ultrafiltration. Clinical parameters and genetic data were evaluated as potential predictors. Two linear regression models were developed using training cohort data (n = 40): model 1 incorporated Cpt as the primary predictor, whereas model 2 used the daily perampanel dose. Internal validation was performed using the validation cohort (n = 20). The association between Cpf and central nervous system adverse events was also assessed. Results: Model 1 included serum creatinine levels and treatment duration, and it demonstrated strong performance (adjusted R 2 = 0.808). Model 2 incorporated interleukin-6 and showed moderate performance (adjusted R 2 = 0.662). Both models demonstrated good internal validity, and the predicted Cpf correlated with the observed values in the validation cohort. Cpf tended to be higher in patients with central nervous system adverse events ( P = 0.195). Conclusions: Two linear regression models were developed to estimate unbound perampanel concentration (Cpf) using routine clinical data. These models may facilitate the therapeutic drug monitoring of perampanel when experimentally determined unbound perampanel concentrations are unavailable.