AUTHOR=Conti Valeria , Izzo Viviana , Russillo Maria Claudia , Picillo Marina , Amboni Marianna , Scaglione Cesa L. M. , Nicoletti Alessandra , Cani Ilaria , Cicero Calogero E. , De Bellis Emanuela , Charlier Bruno , Giudice Valentina , Somma Gerardina , Corbi Graziamaria , Barone Paolo , Filippelli Amelia , Pellecchia Maria Teresa 

TITLE=Gender Differences in Levodopa Pharmacokinetics in Levodopa-Naïve Patients With Parkinson’s Disease

JOURNAL=Frontiers in Medicine

VOLUME=9

YEAR=2022

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.909936

DOI=10.3389/fmed.2022.909936

ISSN=2296-858X

ABSTRACT=<sec><title>Background</title><p>Levodopa (LD) is the most effective drug in the treatment of Parkinson’s disease (PD). Unfortunately, prolonged use of LD leads to complications, mainly motor/non-motor fluctuations (MNMF) and dyskinesias (DYS). Women seem more prone to develop such LD-related complications. Nonetheless, there is a paucity of prospective studies examining gender-related predictors of MNMF and DYS. Among several factors, which concur with a very complex scenario, changes in LD pharmacokinetics influence the drug’s effectiveness. The present study aimed to assess gender-related differences in LD pharmacokinetics in patients with PD at their first-ever intake of LD.</p></sec><sec><title>Materials and Methods</title><p>This is a multicentric study enrolling patients with PD, who were LD-naïve and received a single dose of LD/benserazide (100/25 mg) formulation. All participants gave their written informed consent, and the study was approved by the local Ethics Committees. To measure plasma LD concentrations and pharmacokinetic parameters (AUC, Cmax, Tmax, <italic>t</italic><sub>1/2</sub>), fasting blood samples were collected before drug intake and then at 8-time points until 260 min. LD concentrations were measured by ultra-high-performance liquid chromatography coupled with mass spectrometry (UHPLC-MS). Multiple linear regression analyses were performed to identify the predictors of the parameters.</p></sec><sec><title>Results</title><p>Thirty-five patients (16 women and 19 men) were consecutively enrolled. Area under curve (AUC) and maximum plasma concentration (Cmax) were significantly higher in women than men (<italic>p</italic> = 0.0006 and <italic>p</italic> = 0.0014, respectively). No statistically significant difference was found regarding Tmax and <italic>t</italic><sub>1/2</sub>. Multiple linear regression analyses revealed that female sex (β = 1.559116, 95% CI 0.8314479 2.286785; <italic>p</italic> &lt; 0.0001) and body mass index (BMI) (β = −0.0970631, 95% CI −0.1733004 −0.0208258; <italic>p</italic> = 0.014) significantly predicted AUC. Only female sex significantly predicted Cmax (β = 1,582.499, 95% CI 731.581 2,433.417; <italic>p</italic> = 0.001). Moreover, only BMI significantly predicted <italic>t</italic><sub>1/2</sub> (β = 0.0756267, 95% CI 0.0143407 0.1369126; <italic>p</italic> = 0.017). Stratifying by gender, BMI was confirmed to significantly predict <italic>t</italic><sub>1/2</sub> in women (β = 0.1300486, 95% CI 0.0172322 0.242865; <italic>p</italic> = 0.027), but not in men.</p></sec><sec><title>Conclusion</title><p>This study provides novel insights on gender differences in LD pharmacokinetics, possibly contributing to the later development of motor complications and dyskinesia in PD.</p></sec>