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Effect of Carbidopa Dose on Levodopa Pharmacokinetics With and Without Catechol-O-Methyltransferase Inhibition in Healthy Subjects

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Abstract

Background and Objectives

The treatment of Parkinson’s disease (PD) is still symptomatic since disease-modifying treatments for PD are not available. Oral levodopa is the gold standard for the treatment of PD motor symptoms. However, incomplete and fluctuating plasma exposure of levodopa leads to suboptimal treatment of the symptoms. The main objective of this study was to investigate to what extent increased carbidopa doses (50 and 100 mg) increase the plasma levels of 100-mg immediate-release (IR) levodopa compared to a 25-mg carbidopa dose with and without co-administration of 200 mg entacapone.

Methods

A double-blind, placebo-controlled, randomized, crossover, phase I, pharmacokinetic study with 25 healthy volunteers was conducted. In addition, a semi-mechanistic pharmacokinetic model was built to theoretically evaluate the effect of inhibiting aromatic amino acid decarboxylase (AADC) and catechol-O-methyltransferase (COMT) mediated metabolism of levodopa on the exposure of levodopa.

Results

The effect of increased carbidopa doses 50 and 100 mg on the total exposure (AUC) of 100 mg IR levodopa was +29% and +36%, respectively, when entacapone was co-administered. Without entacapone, the corresponding increases were +13% and +17%. With entacapone co-administration, the increased carbidopa dose also clearly increased levodopa trough concentration. There was no significant effect on the peak concentrations of levodopa.

Conclusions

Increasing carbidopa doses significantly increased the exposure and reduced the fluctuation of IR levodopa in plasma during simultaneous COMT inhibition with entacapone. Theoretical pharmacokinetic simulations suggested that the plasma profile of oral IR levodopa can be even further improved by optimizing AADC and COMT inhibition.

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Authors and Affiliations

  1. Orion Corporation Orion Pharma, Espoo, Finland

    Johanna Tuunainen

  2. Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland

    Noora Sjöstedt & Marjo Yliperttula

  3. Orion Corporation Orion Pharma, Kuopio, Finland

    Mikko Vahteristo

  4. Orion Corporation Orion Pharma, Turku, Finland

    Juha Ellmén, Mikko Kuoppamäki & Juha Rouru

Authors
  1. Johanna Tuunainen
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Corresponding author

Correspondence to Johanna Tuunainen.

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Acknowledgements

The authors thank the participants, investigators, trial-site staff, and Orion Pharma employees involved in the studies. Hanna Wartiovaara is acknowledged for the supervision of the bioanalytical work. Mikko Koskinen is acknowledged for reviewing the manuscript.

Author contributions

Participated in clinical study design and study conduct: JT, MV, JE, JK and JR. Performed data analysis and modelling: JT, NS, MV and MY. All authors contributed to the writing of the manuscript and approved the final version for publication.

Funding

The clinical studies were sponsored by Orion Corporation, Orion Pharma. No funding was received for the preparation of this article.

Availability of data and material

The study data are available from the corresponding author upon reasonable request.

Code availability

Upon reasonable request.

Conflict of interest

Johanna Tuunainen, Mikko Vahteristo, Juha Ellmén, Mikko Kuoppamäki, and Juha Rouru were employees of Orion Corporation, Orion Pharma, Finland, at the time of study conduct. Mikko Vahteristo and Mikko Kuoppamäki own stock in Orion Corporation. Noora Sjöstedt and Marjo Yliperttula declare that they have no conflict of interest.

Ethics approval

All studies were conducted in accordance with the International Council for Harmonization Good Clinical Practice, the principles of the Declaration of Helsinki, and all applicable national regulations. The presented study was approved by the ethics committee of the Hospital District of Helsinki and Uusimaa (250/13/03/00/2008). The studies used for pharmacokinetic model building were approved by the Manchester independent research ethics committee (ME1004/3097001) and the ethics committee of the Hospital District of Helsinki and Uusimaa.

Consent to participate

For all clinical studies described in the article, informed consent was obtained from the participants.

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Not applicable.

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Tuunainen, J., Sjöstedt, N., Vahteristo, M. et al. Effect of Carbidopa Dose on Levodopa Pharmacokinetics With and Without Catechol-O-Methyltransferase Inhibition in Healthy Subjects. Eur J Drug Metab Pharmacokinet 48, 23–34 (2023). https://doi.org/10.1007/s13318-022-00800-w

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