Dataset Information

Sex Is the Main Determinant of Levodopa Clinical Pharmacokinetics: Evidence from a Large Series of Levodopa Therapeutic Monitoring.

ABSTRACT:

Background

Different studies, mostly with limited cohorts, have suggested the effects of patients' characteristics on levodopa (LD) pharmacokinetics.

Objective

We primarily aimed at investigating in a large population the relationship between patients' features and LD kinetic variables, to assess the main demographic and clinical predictors of LD clinical pharmacokinetics.

Methods

The study was retrospective, based on data collected from subjects with parkinsonism on chronic LD undergoing LD therapeutic monitoring (TM). LD TM includes serial quantitative motor tests and blood samples to measure plasma drug concentrations after each subject's chronically taken first-morning LD dose intake.

Results

Five hundred patients, 308 males (61.6%), mean (SD) age of 65 (10.1) years were included. Parkinsonian symptoms and LD therapy lasted 5.5 (4.5) and 3.4 (3.9) years, respectively. MDS-UPDRS part III "off" score was 28.8 (15.2). LD dose was 348.2 (187.1) mg/day. From multiple linear regression analysis, test dose, sex, type of LD decarboxylase inhibitor, weight and MDS-UPDRS part III score were linear predictors of both LD peak plasma concentration (Cmax) (R2 = 0.52) and area under the 3-h plasma concentration-time curve (AUC) (R2 = 0.71), while age was a further predictor only for AUC. Besides test dose, sex was the strongest independent contributing variable to LD AUC, which resulted 27% higher in females compared to males.

Conclusion

This is the largest collection of data on the relationship between demographic and clinical-therapeutic variables and LD kinetics in patients with parkinsonian symptoms. As a main clinically practical finding, women might require a 25% reduced weight-normalized LD dose compared with men to achieve the same LD bioavailability.

SUBMITTER: Contin M

PROVIDER: S-EPMC9837688 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Sex Is the Main Determinant of Levodopa Clinical Pharmacokinetics: Evidence from a Large Series of Levodopa Therapeutic Monitoring.

Contin Manuela M Lopane Giovanna G Belotti Laura M B LMB Galletti Margherita M Cortelli Pietro P Calandra-Buonaura Giovanna G

Journal of Parkinson's disease 20220101 8

<h4>Background</h4>Different studies, mostly with limited cohorts, have suggested the effects of patients' characteristics on levodopa (LD) pharmacokinetics.<h4>Objective</h4>We primarily aimed at investigating in a large population the relationship between patients' features and LD kinetic variables, to assess the main demographic and clinical predictors of LD clinical pharmacokinetics.<h4>Methods</h4>The study was retrospective, based on data collected from subjects with parkinsonism on chroni ...[more]

PMID: 36373294

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Project description:Parkinson's disease (PD) is a progressive, neurodegenerative disorder primarily affecting dopaminergic neuronal systems, with impaired motor function as a consequence. The most effective treatment for PD remains the administration of oral levodopa (LD). Long-term LD treatment is frequently associated with motor fluctuations and dyskinesias, which exert a serious impact on a patient's quality of life. The aim of our study was to determine the pharmacokinetics of LD: used as monotherapy or in combination with ropinirole, in patients with advanced PD. Furthermore, an effect of ropinirole on the pharmacokinetics of 3-OMD (a major LD metabolite) was assessed. We also investigated the correlation between the pharmacokinetic parameters of LD and 3-OMD and the occurrence of motor complications. Twenty-seven patients with idiopathic PD participated in the study. Thirteen patients received both LD and ropinirole, and fourteen administered LD monotherapy. Among 27 patients, twelve experienced fluctuations and/or dyskinesias, whereas fifteen were free of motor complications. Inter- and intra-individual variation in the LD and 3-OMD concentrations were observed. There were no significant differences in the LD and 3-OMD concentrations between the patients treated with a combined therapy of LD and ropinirole, and LD monotherapy. There were no significant differences in the LD concentrations in patients with and without motor complications; however, plasma 3-OMD levels were significantly higher in patients with motor complications. A linear one-compartment pharmacokinetic model with the first-order absorption was adopted for LD and 3-OMD. Only mean exit (residence) time for 3-OMD was significantly shorter in patients treated with ropinirole. Lag time, V/F, CL/F and tmax of LD had significantly lower values in patients with motor complications. On the other hand, AUC were significantly higher in these patients, both for LD and 3-OMD. 3-OMD Cmax was significantly higher in patients with motor complications as well. Our results showed that ropinirole does not influence LD or 3-OMD concentrations. Higher 3-OMD levels play a role in inducing motor complications during long-term levodopa therapy.

Dataset Information

Sex Is the Main Determinant of Levodopa Clinical Pharmacokinetics: Evidence from a Large Series of Levodopa Therapeutic Monitoring.

Background

Objective

Methods

Results

Conclusion

Publications

Sex Is the Main Determinant of Levodopa Clinical Pharmacokinetics: Evidence from a Large Series of Levodopa Therapeutic Monitoring.

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