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

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.Electronic supplementary materialThe online version of this article (10.1007/s00228-018-2497-2) contains supplementary material, which is available to authorized users.

Model-based optimization of controlled release formulation of levodopa for Parkinson’s disease

“…The occurrence of a double peak in levodopa plasma concentrations has been previously reported 30 , 31 , 34 , 40 , 41 and was attributed to the presence of dissolved levodopa in the stomach, which interferes with gastric emptying 30 , 31 . The mechanism of interference is not entirely understood 40 , and exhibits large variability 30 , 31 ; in our dataset 5 individuals out of 7 exhibits a double peak (Fig. S1 , supplementary information).…”

“…Following Oberle et al 28 , stomach emptying is modeled as a first-order process. However, dissolved levodopa can cause erratic gastric emptying 30 , 31 , 34 , 35 , 40 , 41 , that manifests by temporarily halting the emptying from the stomach (a ’lag’ in emptying). The erratic emptying exhibits high inter- and intra-subject variability and might not always exist.…”

“…The erratic emptying exhibits high inter- and intra-subject variability and might not always exist. The mechanism that causes the lag in gastric emptying is not yet known 40 , and therefore we empirically incorporate the lag in the present model similarly to the empirical model of Ogungbenro et al 41 . Specifically, the erratic emptying is described as a single lag that begins minutes after ingestion, and lasts for minutes.…”

Personalized Medicine Approach in Treating Parkinson’s Disease, Using Oral Administration of Levodopa/Carbidopa Microtablets in Clinical Practice

“…Since the introduction of levodopa in the 1960s, it has been the gold standard for PD treatment [ 5 ]. However, as the disease progresses, the pharmacological response may vary, requiring higher and more frequent doses of levodopa [ 2 , 6 , 7 , 8 ]. Patients may develop motor fluctuations over time, manifested as end-of-dose deterioration and/or dyskinesia, affecting nearly half of PD patients after five years of treatment [ 2 , 9 , 10 ].…”

“…By implementing the personalized medicine model for PD, the levodopa dose would be fractionated to smaller doses, taken at the onset of motor fluctuations and allowing for constant modification due to the dynamic nature of the disease [ 11 , 12 ]. One such possibility is the use of levodopa/carbidopa 5/1.25 mg microtablets (LC-5) in an electronic dose dispenser [ 13 ], allowing the individualization and fine tuning of the dose size and interval, as well as a more stable levodopa plasma concentration, compared with standard tablet formulations [ 7 , 8 , 14 , 15 , 16 ]. The dose dispenser is equipped with an alarm, to facilitate treatment adherence, and an optional diary-like function for self-reporting [ 9 ].…”