Population pharmacokinetics of levodopa/carbidopa microtablets in healthy subjects and Parkinson’s disease patients

OBJECTIVES: Low dose, dispersible, levodopa/carbidopa microtablets with an automatic dose dispenser have been developed to facilitate individualized levodopa treatment. The aim of this study was to characterize the pharmacokinetics (PK) of levodopa and carbidopa after microtablet administration, and evaluate the impact of potential covariates. METHODS: The population PK analysis involved data from 18 healthy subjects and 18 Parkinson’s disease patients included in two single-dose, open-label levodopa/carbidopa microtablet studies. The analysis was carried out using non-linear mixed effects modeling. Bodyweight was included on all disposition parameters according to allometric scaling. Potential influence of additional covariates was investigated using graphical evaluation and adjusted adaptive least absolute shrinkage and selection operator. RESULTS: Dispositions of levodopa and carbidopa were best described by a two- and one-compartment model respectively. Double-peak profiles were described using two parallel absorption compartments. Levodopa apparent clearance was found to decrease with increasing carbidopa dose (15% lower with 75 compared to 50 mg of carbidopa) and disease stage (by 18% for Hoehn and Yahr 1 to 4). Carbidopa apparent clearance was found to decrease with age (28% between the age of 60 and 80 years). An external evaluation showed the model to be able to reasonably well predict levodopa concentrations following multiple-dose microtablet administration in healthy subjects. CONCLUSIONS: The presented models adequately described the PK of levodopa and carbidopa, following microtablet administration. The developed model may in the future be combined with a pharmacokinetic-pharmacodynamic target and used for individualized dose selection, utilizing the flexibility offered by the microtablets. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00228-018-2497-2) contains supplementary material, which is available to authorized users.