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Update on Levodopa/Carbidopa Intestinal Gel Infusion

Published Online: July 15th 2012 European Neurological Review, 2012;7(Suppl. 1):13–6 DOI: http://doi.org/10.17925/ENR.2012.07.S1.13
Authors: Dag Nyholm
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Abstract:
Overview

Recent data on levodopa/carbidopa intestinal gel (LCIG) infusion are discussed in this article. LCIG infusion provides improvements in ‘off’ time and dyskinesia via continuous dopaminergic stimulation (CDS). In the long-term, LCIG infusion appears to maintain efficacy without the need to increase dosages. The growing number of publications on LCIG infusion shows the increasing experience and interest in this therapy. The new data demonstrate the effects of using LCIG infusion in combination with catechol-O-methyl transferase inhibitors, and technical improvements to the pump system (e.g., to the tubing). Despite the invasive nature of LCIG infusion, nearly all patients would recommend this treatment. Furthermore, a number of larger-scale studies on this particular CDS therapy are in progress.

Keywords

Parkinson’s disease, levodopa, continuous dopaminergic stimulation, levodopa/carbidopa intestinal gel, motor fluctuations

Article:

In 1975, it was shown that achieving stable plasma levodopa levels by continuous intravenous infusion of levodopa rapidly stabilised motor fluctuations in Parkinson’s disease (PD) patients.1 However, intravenous levodopa infusion did not become a practical treatment option in PD because of the technical complexity of administration.2 In the mid-1980s, it was shown that enteral (duodenal/jejunal) infusion of levodopa achieved stable plasma levodopa concentrations and reduced motor fluctuations,3 but the large volumes of levodopa/carbidopa solutions involved were cumbersome and impractical. It was only when a gel formulation of levodopa/carbidopa was developed that enteral infusion became a viable therapy. This levodopa/carbidopa intestinal gel (LCIG) infusion therapy has undergone further development and testing in patients.4,5 The recent data on this therapy, collected until May 2011, are discussed in this article.

Recent Findings on Levodopa/Carbidopa Intestinal Gel Infusion Pharmacokinetics and Pharmacodynamics
Several recent studies have examined the pharmacokinetics and pharmacodynamics of LCIG infusion treatment. One of these studies aimed to identify and estimate characteristic parameters of a population pharmacokinetic-pharmacodynamic model for LCIG infusion, in order to better understand the pharmacological properties of this levodopa formulation.6 A model was developed based on pooled data from three studies in patients with advanced Parkinson’s disease (APD).

The study showed that absorption of LCIG can be adequately described with first-order absorption (mean absorption time of 28.5 minutes) with a bioavailability of 88 % and a lag time of 2.9 minutes. The parameters were relatively well determined, with standard errors of 4–43 %. The best pharmacodynamic model was of the effect compartment sigmoid Emax type with a steep sigmoidicity coefficient (Hill=11.6), a half-life of effect delay of 21 minutes, a concentration at 50 % effect of 1.55 mg/l, and an Emax of 2.39 units on the treatment response scale. This model may be a first step towards model-guided treatment individualisation of LCIG infusion.

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Disclosure

Dag Nyholm serves as a consultant to Abbott, who sponsored research in which he served as principal investigator. He also serves as a consultant to AstraZeneca and Sensidose AB; has received honoraria from H. Lundbeck AB; has received speaker fees from NordicInfu Care; has received research support from Abbott and Kibion AB; is co-founder and stock-owner in Jemardator AB; and receives remuneration from the website netdoktor.se for participation in an expert panel.

Correspondence

Dag Nyholm, Department of Neuroscience, Neurology, Uppsala University Hospital, SE-75185 Uppsala, Sweden. E: dag.nyholm@neuro.uu.se

Support

The V International Forum on Parkinson’s Disease (Helsinki, Finland, 6–7 May 2011) was funded by an unrestricted educational grant from Abbott. Abbott funded the development of this supplement by ESP Bioscience (Crowthorne, UK). Emily Chu and Nicole Meinel of ESP Bioscience provided medical writing and editorial support to the author in the development of this publication. Abbott had the opportunity to review and comment on the publication’s content; however, all decisions regarding content were made by the author.

Acknowledgements

: The V International Forum on Parkinson’s Disease (Helsinki, Finland, 6–7 May 2011) was funded by an unrestricted educational grant from Abbott. Abbott funded the development of this supplement by ESP Bioscience (Crowthorne, UK). Emily Chu and Nicole Meinel of ESP Bioscience provided medical writing and editorial support to the author in the development of this publication. Abbott had the opportunity to review and comment on the publication’s content; however, all decisions regarding content were made by the author.

Received

2013-06-22T00:00:00

References

  1. Shoulson I, Glaubiger GA, Chase TN, On-off response. Clinical and biochemical correlations during oral and intravenous levodopa administration in parkinsonian patients, Neurology, 1975;25:1144–8.
  2. Nyholm D, Aquilonius SM, Levodopa infusion therapy in Parkinson disease: state of the art in 2004, Clin Neuropharmacol, 2004;27:245–56.
  3. Kurlan R, Rubin AJ, Miller C, et al., Duodenal delivery of levodopa for on-off fluctuations in parkinsonism: preliminary observations, Ann Neurol, 1986;20:262–5.
  4. Nyholm D, Enteral levodopa/carbidopa gel infusion for the treatment of motor fluctuations and dyskinesias in advanced Parkinson’s disease, Expert Rev Neurother, 2006;6:1403–11.
  5. Nyholm D, Lewander T, Johansson A, et al., Enteral levodopa/carbidopa infusion in advanced Parkinson disease: long-term exposure, Clin Neuropharmacol, 2008;31:63–73.
  6. Westin J, Nyholm D, Pålhagen S, et al., A pharmacokineticpharmacodynamic model for duodenal levodopa infusion, Clin Neuropharmacol, 2011;34:61–5.
  7. Nyholm D, Johansson A, Aquilonius SM, et al., Complexity of motor response to different doses of duodenal levodopa infusion in Parkinson disease, Clin Neuropharmacol, 2012;35:6–14.
  8. Antonini A, Bondiolotti G, Natuzzi F, Bareggi SR, Levodopa and 3-OMD levels in Parkinson patients treated with Duodopa, Eur Neuropsychopharmacol, 2010;20:683–7.
  9. Nyholm D, Johansson A, Lennernäs H, Askmark H, Levodopa infusion combined with entacapone or tolcapone in Parkinson disease: a pilot trial, Eur J Neurol, 2012;19:820–6.
  10. Lai CW, Barlow R, Barnes M, Hawthorne AB, Bedside placement of nasojejunal tubes: a randomised-controlled trial of spiral- vs straight-ended tubes, Clin Nutr, 2003;22:267–70.
  11. Schrader C, Böselt S, Wedemeyer J, et al., Asparagus and jejunal-through-PEG: an unhappy encounter in intrajejunal levodopa infusion therapy, Parkinsonism Relat Disord, 2011;17:67–9.
  12. Nyman R, Lundgren D, Nyholm D, Soft tissue-anchored transcutaneous port attached to an intestinal tube for longterm gastroduodenal infusion of levodopa/carbidopa in Parkinson disease, J Vasc Interv Radiol, 2009;20:500–5.
  13. Meppelink AM, Nyman R, van Laar T, et al., Transcutaneous port for continuous duodenal levodopa/carbidopa administration in Parkinson’s disease, Mov Disord, 2011;26:331–4.
  14. Nyholm D, Klangemo K, Johansson A, Levodopa/carbidopa intestinal gel infusion long-term therapy in advanced Parkinson’s disease, Eur J Neurol, 2012;19:1079–85.
  15. Scott B, Nyholm D, Patient-perceived retrospective outcome of duodenal levodopa infusion in advanced Parkinson’s disease, European Neurological Journal, 2010;2:1–8.
  16. Merola A, Zibetti M, Angrisano S, et al., Comparison of subthalamic nucleus deep brain stimulation and Duodopa in the treatment of advanced Parkinson’s disease, Mov Disord, 2011;26:664–70.

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