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Population pharmacokinetics of levodopa/carbidopa microtablets in healthy subjects and Parkinson’s disease patients
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.ORCID iD: 0000-0003-0302-6946
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.ORCID iD: 0000-0001-9776-7715
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2018 (English)In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 74, no 10, p. 1299-1307Article in journal (Refereed) Published
Abstract [en]

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 50mg 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 80years). 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.

Place, publisher, year, edition, pages
2018. Vol. 74, no 10, p. 1299-1307
National Category
Neurology
Identifiers
URN: urn:nbn:se:uu:diva-343034DOI: 10.1007/s00228-018-2497-2ISI: 000444387700009PubMedID: 29882153OAI: oai:DiVA.org:uu-343034DiVA, id: diva2:1185463
Funder
VINNOVAAvailable from: 2018-02-25 Created: 2018-02-25 Last updated: 2018-11-13Bibliographically approved
In thesis
1. New Approaches for Levodopa Treatment in Parkinson’s Disease
Open this publication in new window or tab >>New Approaches for Levodopa Treatment in Parkinson’s Disease
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Parkinson’s disease (PD) is characterized by degeneration of dopaminergic cells, which results in dopamine depletion. Levodopa is the most effective symptomatic treatment, however, disease progression along with the unfavorable pharmacokinetics of levodopa makes the disease increasingly difficult to treat with time.

This thesis focuses on two new approaches of levodopa treatments, the levodopa/carbidopa microtablets and the levodopa/entacapone/carbidopa intestinal gel, developed for patients with advanced PD.

To evaluate the microtablet pharmacokinetics and pharmacodynamics in advanced PD patients, a clinical study was conducted. Higher levodopa maximum plasma concentration and systemic exposure was observed in patients compared to healthy volunteers. A high variability, with respect to response and duration of effect, was found, highlighting the importance of individual assessment of motor function to optimize treatment effect. A population pharmacokinetic model for levodopa and carbidopa was developed and the impact of covariates were investigated on the pharmacokinetics. Disease stage and increasing carbidopa dose were found to decrease levodopa apparent clearance. Carbidopa apparent clearance was found to decrease with age. An observational study was conducted, including patients treated with microtablets, in order to evaluate the treatment in clinical practice. A majority reported that the dose dispenser simplified their treatment and improved adherence, while the motor function, with respect to bradykinesia and non-troublesome dyskinesia, was mainly improved or unchanged.

To investigate the pharmacokinetics and pharmacodynamics of the newly developed levodopa/entacapone/carbidopa intestinal gel treatment, a clinical trial was conducted, where it was compared to the conventional levodopa/carbidopa infusion. The new treatment was found to allow a lower amount of levodopa administration without worsening the treatment effect. An increasing plasma concentration was observed, and a population model was developed for investigation of appropriate dose adjustments. The conclusion was that the continuous maintenance dose could be decreased by approximately 35%, on a population level, compared to the patients’ usual dose on the conventional treatment. An effect from entacapone was identified in all individuals, regardless of catechol-O-methyl transferase genotype (rs4680).

To conclude, both new treatments are promising alternatives to current strategies and the developed models may in the future be used for model-based treatment optimization.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 84
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1437
Keywords
Parkinson’s disease, Pharmacokinetics, Pharmacodynamics, Population modeling, Levodopa, Carbidopa, Entacapone, Microtablets, Intestinal infusion
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-343036 (URN)978-91-513-0256-0 (ISBN)
Public defence
2018-04-20, Rudbeckssalen, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2018-03-27 Created: 2018-02-28 Last updated: 2018-04-24

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Senek, MarinaNyholm, DagNielsen, Elisabet I.

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