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=Volume 9 - 2022

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=Background. 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 effectiveness. The present study aimed to assess gender-related differences in LD pharmacokinetics in PD patients at their first ever intake of LD. 
Methods. This is a multicentric study enrolling PD patients, 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, t1/2), fasting blood samples were collected before drug intake and then at 8 time points until 260 minutes. LD concentrations were measured by ultra-high performance liquid chromatography coupled with mass spectrometry. Multiple linear regression analyses were performed to identify the predictors of the parameters.
Results. Thirty-five patients (16 women and 19 men) were consecutively enrolled. AUC and Cmax were significantly higher in women than men (p=0.0006 and p=0.0014, respectively). No statistically significant difference was found regarding Tmax and t1/2. Multiple linear regression analyses revealed that female sex (β =  1.559116, 95% CI 0.8314479   2.286785; p <0.0001) and BMI (β = -0.0970631, 95% CI -0.1733004   -0.0208258; p= 0.014) significantly predicted AUC. Only female sex significantly predicted Cmax (β =1582.499, 95% CI 731.581    2433.417; p =0.001). Moreover, only BMI significantly predicted t1/2 (β =0.0756267, 95% CI  0.0143407    0.1369126; p =0.017). Stratifying by gender, BMI was confirmed to significantly predict t1/2 in women (β =0.1300486, 95% CI  0.0172322    0.242865; p =0.027), but not in men. 
Conclusions. This study provides novel insights on gender differences in LD pharmacokinetics, possibly contributing to the later development of motor complications and dyskinesia in PD.