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Continuous Dopaminergic Stimulation in Focus Update on Levodopa/Carbidopa Intestinal Gel Infusion Dag Nyholm Associate Professor, Department of Neuroscience, Neurology, Uppsala University, Uppsala, Sweden Abstract 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 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 for participation in an expert panel. 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: 22 June 2012 Accepted: 6 August 2012 Citation: European Neurological Review, 2012;7(Suppl. 1):13–6 Correspondence: Dag Nyholm, Department of Neuroscience, Neurology, Uppsala University Hospital, SE-75185 Uppsala, Sweden. E: 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 © TOUCH BRIEFINGS 2012 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 E max 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 E max of 2.39 units on the treatment response scale. This model may be a first step towards model-guided treatment individualisation of LCIG infusion. A second, observational study assessed the pharmacokinetics of LCIG infusion therapy and the effects on motor symptoms in five patients with difficult-to-treat dyskinesias. 7 In this non-randomised, partly blinded, investigator-initiated trial, LCIG doses of 80–120 % of individually and clinically optimised dosage were infused during five 4-hour periods. Plasma samples for levodopa determination, video recording for blinded assessment and objective movement analysis were performed every 20 minutes during the first hour of each 4-hour period and every 30 minutes thereafter. In all patients, individual correlations between plasma levodopa concentrations and corresponding motor scores 20–30 minutes after the sampling time were significant (p<0.05) (see Figure 1). Motor scores were generally stable during the 4-hour periods. Scores on the Treatment Response Scale (TRS) were positive even at 80 % of the optimised LCIG dose, which indicates dyskinesia even at this lower-than-optimised dose of LCIG. Measurement of movement time by objective movement analysis showed that the more dyskinetic the patients were, the faster their motor performance. Therefore, motor performance may be improved with moderate dyskinesia versus mild dyskinesia, 13