Population pharmacokinetics of levodopa/carbidopa microtablets in healthy subjects and Parkinson\u2019s disease patients

Marina Senek,Elisabet I Nielsen,Dag Nyholm

doi:10.1007/s00228-018-2497-2

Abstract

ObjectivesLow 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.MethodsThe 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.ResultsDispositions 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.ConclusionsThe 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.

Highlights

In the initial stage of Parkinson’s disease (PD), the effect from levodopa (LD) and carbidopa (CD) treatment is often satisfactory, with a stable motor function that is near normal throughout the day
The patients can become more involved in their treatment, and for the physicians, it can serve as an aid in therapeutic decision-making
The final base model for CD and LD was a one and twocompartment model respectively, with parallel absorption compartments including transit compartments describing absorption delay (ΔOFV of 995 and 240 for CD and LD respectively compared to a model with a single absorption compartment)

Summary

Introduction

In the initial stage of Parkinson’s disease (PD), the effect from levodopa (LD) and carbidopa (CD) treatment is often satisfactory, with a stable motor function that is near normal throughout the day. The dispenser records the dosing history (amount and timing) and indicates if a planned dose is missed. It has a diary function which allows for self-. Eur J Clin Pharmacol (2018) 74:1299–1307 reporting of symptoms that can be viewed by both the patient and the treating physician. The patients can become more involved in their treatment, and for the physicians, it can serve as an aid in therapeutic decision-making This treatment alternative allows the dosages to be highly individualized, but initial investigations have shown that it can be challenging to find the optimal dosing regimen [5]. The model, in combination with a pharmacodynamic model, can be used to visualize the individuals expected time profile of the concentration and effect (size and duration) based on current dosing, and be used to facilitate the tailoring of treatment to the need of individual patients

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