Actively Transported Levodopa Prodrug XP21279

Objective The objectives of this study were to assess the pharmacokinetic profile, efficacy, and safety of XP21279 administered with carbidopa (CD) in subjects with Parkinson disease (PD) experiencing motor fluctuations and explore dose correspondence between CD-levodopa (LD) and XP21279 administered with CD. Methods Subjects received CD-LD 3 or 4 times daily for 2 weeks, followed by XP21279 plus CD 3 times daily for 2 weeks at fixed dosing times, allowing dose adjustment to optimize clinical response, in this multiple-dose, multicenter, open-label, 2-period, sequential-treatment study. Pharmacokinetic parameters, including LD exposure, were assessed over 16 hours on the last day of each treatment period. Levodopa exposure variability was assessed for each treatment using the absolute % deviation from average concentration (Cavg) in each subject. Efficacy assessments included daily self-ratings of OFF time, ON time, and dyskinesias. Results XP21279 provided significantly less variability in LD concentration compared with CD-LD (P < 0.05) in 10 PD subjects with motor fluctuations, consistent with lower peak-to-trough fluctuation for XP21279. Patterns of percentage of subjects OFF were consistent with the LD concentration-time profiles for each respective treatment. Compared with CD-LD treatment, 6 of 10 study completers experienced reduction of 30% or greater in average daily OFF time during the last 4 days in the XP21279 treatment period. XP21279 resulted in an increase in the time spent ON without troublesome dyskinesias, and the mean time to ON after the first morning XP21279 dose was not delayed, as compared with CD-LD. Conclusions XP21279 provided improved pharmacokinetic performance (highlighted by reduction in variability of LD concentration) compared with CD-LD and therefore may provide better control of PD motor fluctuations.