Levodopa in Parkinson’s Disease: A Review of Population Pharmacokinetics/Pharmacodynamics Analysis

Marsot, Amélie; Guilhaumou, Romain; Azulay, J.-P.; Blin, Olivier

doi:10.18433/j30h04

Cited by 16 publications

(16 citation statements)

References 45 publications

(27 reference statements)

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“…The present analysis characterized the pharmacokinetics of LD and CD when administered as dissolved microtablets to PD patients and healthy subjects, and investigated the influence of CD dose and plasma concentration on LD pharmacokinetic parameters as well as other covariate-parameter relationships to describe inter-individual PK differences. Levodopa PK has previously been described with both one- and two-compartmental models [ 23 – 25 ]. A two-compartment model was found to provide the best description of LD in this case (OFV reduced by 147.4 compared to a one-compartment model).…”

Section: Discussionmentioning

confidence: 99%

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

Senek

Nyholm

Nielsen

2018

Eur J Clin Pharmacol

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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.

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Section: Discussionmentioning

confidence: 99%

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

Senek

Nyholm

Nielsen

2018

Eur J Clin Pharmacol

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“…However, it increased up to $51.9 billion in 2017 [3], and is expected to increase more dramatically in the future. The most effective therapeutic option is the administration of l-3,4-dihydroxyphenylalanine (L-DOPA), which can cross the blood‒brain barrier and be metabolized to dopamine [4]. However, all currently available drugs, including L-DOPA, only modulate dopamine levels in PD patients’ brains and are of limited effectiveness in the initial stages of the disease, which can last for 1–5 years [5].…”

Section: Introductionmentioning

confidence: 99%

Amelioration of Mitochondrial Quality Control and Proteostasis by Natural Compounds in Parkinson’s Disease Models

Cho

Kim

Huh

et al. 2019

IJMS

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Parkinson’s disease (PD) is a well-known age-related neurodegenerative disorder associated with longer lifespans and rapidly aging populations. The pathophysiological mechanism is a complex progress involving cellular damage such as mitochondrial dysfunction and protein homeostasis. Age-mediated degenerative neurological disorders can reduce the quality of life and also impose economic burdens. Currently, the common treatment is replacement with levodopa to address low dopamine levels; however, this does not halt the progression of PD and is associated with adverse effects, including dyskinesis. In addition, elderly patients can react negatively to treatment with synthetic neuroprotection agents. Recently, natural compounds such as phytochemicals with fewer side effects have been reported as candidate treatments of age-related neurodegenerative diseases. This review focuses on mitochondrial dysfunction, oxidative stress, hormesis, proteostasis, the ubiquitin‒proteasome system, and autophagy (mitophagy) to explain the neuroprotective effects of using natural products as a therapeutic strategy. We also summarize the efforts to use natural extracts to develop novel pharmacological candidates for treatment of age-related PD.

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“…Long-term levodopa treatment of PD is frequently associated with motor fluctuations and dyskinesias, causing a serious impact on a patient's quality of life [1,2,15,16]. One of the possible means to delay motor complications is to include other classes of antiparkinsonian drugs such as dopamine agonists (DA), catechol-O-methyltransferase (COMT) inhibitors, or monoamine oxidase type B (MAO-B) inhibitors into the treatment regime [1,8].…”

Section: Introductionmentioning

confidence: 99%

“…Parkinson’s disease (PD) is a common neurological disorder affecting 2–3% of the population 65 years of age and older [ 1 ]. The disease is characterized by progressive degeneration of the dopaminergic nigrostriatal system and depletion of dopamine, which results in the core motor symptoms of bradykinesia, rigidity, tremor, and postural instability [ 2 , 3 , 4 ]. Pharmacotherapy of PD constitutes dopaminergic drugs, mainly the dopamine precursor levodopa and dopamine receptor agonists.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of Levodopa and 3-O-Methyldopa in Parkinsonian Patients Treated with Levodopa and Ropinirole and in Patients with Motor Complications

Adamiak-Giera,

Jawień,

Pierzchlińska

et al. 2021

Pharmaceutics

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Parkinson’s disease (PD) is a progressive, neurodegenerative disorder primarily affecting dopaminergic neuronal systems, with impaired motor function as a consequence. The most effective treatment for PD remains the administration of oral levodopa (LD). Long-term LD treatment is frequently associated with motor fluctuations and dyskinesias, which exert a serious impact on a patient’s quality of life. The aim of our study was to determine the pharmacokinetics of LD: used as monotherapy or in combination with ropinirole, in patients with advanced PD. Furthermore, an effect of ropinirole on the pharmacokinetics of 3-OMD (a major LD metabolite) was assessed. We also investigated the correlation between the pharmacokinetic parameters of LD and 3-OMD and the occurrence of motor complications. Twenty-seven patients with idiopathic PD participated in the study. Thirteen patients received both LD and ropinirole, and fourteen administered LD monotherapy. Among 27 patients, twelve experienced fluctuations and/or dyskinesias, whereas fifteen were free of motor complications. Inter- and intra-individual variation in the LD and 3-OMD concentrations were observed. There were no significant differences in the LD and 3-OMD concentrations between the patients treated with a combined therapy of LD and ropinirole, and LD monotherapy. There were no significant differences in the LD concentrations in patients with and without motor complications; however, plasma 3-OMD levels were significantly higher in patients with motor complications. A linear one-compartment pharmacokinetic model with the first-order absorption was adopted for LD and 3-OMD. Only mean exit (residence) time for 3-OMD was significantly shorter in patients treated with ropinirole. Lag time, V/F, CL/F and tmax of LD had significantly lower values in patients with motor complications. On the other hand, AUC were significantly higher in these patients, both for LD and 3-OMD. 3-OMD Cmax was significantly higher in patients with motor complications as well. Our results showed that ropinirole does not influence LD or 3-OMD concentrations. Higher 3-OMD levels play a role in inducing motor complications during long-term levodopa therapy.

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Levodopa in Parkinson’s Disease: A Review of Population Pharmacokinetics/Pharmacodynamics Analysis

Cited by 16 publications

References 45 publications

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

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

Amelioration of Mitochondrial Quality Control and Proteostasis by Natural Compounds in Parkinson’s Disease Models

Pharmacokinetics of Levodopa and 3-O-Methyldopa in Parkinsonian Patients Treated with Levodopa and Ropinirole and in Patients with Motor Complications

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