Plasma concentration threshold and risk factors for amantadine-induced central nervous system toxicity in Parkinson’s disease

Background Amantadine is an effective treatment for Parkinson's disease (PD), yet its clinical utility is often limited by central nervous system (CNS) toxicity, particularly in elderly patients and those with renal impairment. The precise relationship between plasma amantadine concentration and the onset of CNS toxicity remains poorly defined. Objective To identify clinical risk factors for amantadine-induced CNS toxicity and to explore the diagnostic value of plasma amantadine concentration as a predictor of toxicity. Methods This cross-sectional study analyzed 92 patients with PD receiving amantadine (46 with CNS toxicity; 46 controls). Plasma amantadine concentrations were determined using gas chromatography. Multivariable logistic and linear regression models were employed to identify predictors of CNS effects and amantadine exposure. A clinical nomogram was developed, and receiver operating characteristic (ROC) analysis was used to evaluate discriminatory performance. Results Advanced age, higher amantadine dosage, and elevated serum creatinine were significantly associated with both the incidence of CNS toxicity and higher plasma concentrations. Nonlinear modeling indicated a sharp increase in the probability of CNS toxicity in patients aged ≥77 years or with creatinine clearance <40 mL/min. ROC analysis demonstrated excellent discrimination (AUC 0.996), with an exploratory threshold of 1776 ng/mL identified for predicting CNS toxicity. Conclusions CNS toxicity from amantadine is driven by a complex interplay of age-related and pharmacokinetic factors. Our proposed nomogram and concentration threshold provide a framework for individualized dosing and proactive monitoring to enhance treatment safety in vulnerable PD populations.