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.

Keywords: Levodopa; dopa decarboxylase inhibitors; levodopa therapeutic monitoring; levodopa-induced dyskinesias; pharmacodynamics; pharmacokinetics; sex.

Fig. 1

Box plots of levodopa: A) peak plasma concentration; B) area under the 3-hour plasma concentration-time curve; C) time to peak plasma concentration; D) test dose, in milligram per kilogram, by different test doses, in milligram. Box plots depict the range between the 25th and 75th percentiles of the data. The horizontal line marks the median value; capped bars indicate 10th–90th percentiles. Black circles represent outlying values. The number of patients for each test dose is reported in brackets.

Fig. 2

Scatter plots of the relationship between levodopa test dose in milligram per kilogram and: A) levodopa area under the 3-h plasma concentration-time curve; B) levodopa peak plasma concentration. The bold black line indicates linear prediction; gray lines indicate 95% confidence intervals.

Fig. 3

Scatter plots of the relationship between levodopa peak plasma concentration and matched area under the 3-hour plasma concentration-time curve. The bold black line indicates linear prediction; gray lines indicate 95% confidence intervals.

Fig. 4

Box plots of levodopa: A) peak plasma concentration; B) area under the 3-h plasma concentration-time curve, both normalized for weight-adjusted test dose by time to peak plasma concentration. Box plots depict the range between the 25th and 75th percentiles of the data. The horizontal line marks the median value; capped bars indicate 10th–90th percentiles. Black circles represent outlying values. p, significance of comparison by Mann-Whitney U test.

Fig. 5

Box plots of levodopa: A) peak plasma concentration; B) area under the 3-h plasma concentration-time curve, both normalized for weight-adjusted test dose by sex (upper section) and dopa decarboxylase inhibitor (lower section). Box plots depict the range between the 25th and 75th percentiles of the data. The horizontal line marks the median value; capped bars indicate 10th–90th percentiles. Black circles represent outlying values. p, significance of comparison by Mann-Whitney U test.