In a 2-year longitudinal study of 28 levodopa‑naïve Parkinson's patients, women had significantly higher levodopa AUC and Cmax than men, and in women (but not men) higher exposure correlated with greater wearing‑off and dyskinesia.

Provides clinically actionable evidence that sex-specific levodopa pharmacokinetics predispose women to motor complications, supporting early plasma monitoring and sex‑adjusted dosing to reduce levodopa-related adverse effects and personalize therapy.

INTRODUCTION: Women with Parkinson's Disease (PD) have higher plasma exposure to levodopa and are particularly prone to developing complications during chronic levodopa therapy. However, there are no longitudinal studies focusing on differences in levodopa pharmacokinetics and their correlation with clinical outcomes. This multicenter longitudinal study aimed to investigate sex-related differences in levodopa pharmacokinetics in levodopa-naïve PD patients, and to evaluate relationships with levodopa-related complications. METHODS: After a single dose of levodopa/DOPA-decarboxylase inhibitor, blood samples were collected at baseline and at two-year follow-up to measure pharmacokinetic parameters using UHPLC-MS. Clinical assessment included wearing-off Questionnaire and MDS-UPDRS scale. Multiple linear regression analyses were performed to identify predictors of pharmacokinetic parameters and levodopa-related complications. RESULTS AND DISCUSSION: The study population consisted of 28 PD patients (18 men, 10 women) followed for 2 years from the start of levodopa therapy. No differences were found between the sexes in clinical characteristics, daily levodopa-dosage, and use of other antiparkinsonian drugs. AUC and Cmax were higher in females than in males (p < 0.001), and sex influenced both of these parameters regardless of whether pharmacokinetic analysis was performed at baseline or at follow-up. Female sex was the best predictor of AUC and Cmax. DYS was found in 20% of females but in no males, and 90% of females showed wearing-off compared to 50% of males (p = 0.022). In females but not in males, the presence of wearing -off was correlated with AUC and Cmax at baseline and after 2 years of treatment. Compared to men, women with PD showed higher plasma levodopa levels since the initial administration and after chronic treatment. Measuring exposure to levodopa may be useful for optimising levodopa dosage since the start of treatment, thus preventing levodopa-related complications.