Levodopa infusion combined with entacapone or tolcapone in Parkinson disease: a pilot trial D. Nyholm a , A. Johansson a , H. Lennerna ¨s b and H. Askmark a a Department of Neuroscience, Neurology, Uppsala University, Uppsala; and b Department of Pharmacy, Uppsala University, Uppsala, Sweden See editorial by Klostermann, on page 795. Keywords: dyskinesias, entacapone, intestinal infusion, levodopa/carbidopa, Parkinson disease, pharmacokinetics, tolcapone Received 28 July 2011 Accepted 30 September 2011 Background and purpose: Catechol-O-methyltransferase inhibitors may be used to decrease levodopa requirement. The objective was to investigate whether the levo- dopa/carbidopa intestinal gel infusion dose can be reduced by 20% without worsening of motor fluctuations and levodopa concentration stability when oral catechol-O- methyltransferase inhibitors are added. Methods: A short-term, randomized, partly blinded, crossover, investigator-initiated clinical trial was performed, with levodopa/carbidopa intestinal gel combined with oral entacapone and tolcapone on two different days in 10 patients. The primary outcome measure was difference in coefficient of variation of levodopa in plasma between levodopa/carbidopa, levodopa/carbidopa/entacapone, and levodopa/carbid- opa/tolcapone. The secondary outcome measures other pharmacokinetic variables, patient-reported outcome, and blinded analysis of motor performance. Results: Variation of plasma levodopa concentrations did not differ significantly between the treatments. The treatments did not differ regarding motor performance. Levodopa concentrations were significantly higher using tolcapone. Concentrations of the metabolite 3-O-methyldopa decreased gradually during catechol-O-methyltransferase inhibition. Conclusions: According to this small, short-term pilot study, oral catechol-O-meth- yltransferase inhibitors administered in 5-h intervals may be useful in cases where levodopa/carbidopa intestinal gel dose reduction is wanted. Stability of plasma levo- dopa levels is not significantly altered, and off-time is not increased when decreasing the levodopa/carbidopa intestinal gel dose by 20%. Rather, the dose should probably be decreased more than 20%, especially under tolcapone co-treatment, to avoid increased dyskinesias with time. Introduction Oral administration of levodopa in combination with a peripheral inhibitor of aromatic amino acid decarbox- ylase, such as carbidopa, is the basic treatment strategy in ParkinsonÕs disease (PD). Several attempts have been made to prolong the efficacy of each levodopa dose or to smooth out the fluctuations in levodopa pharmaco- kinetics [1]. Inhibitors of catechol-O-methyl-transferase (COMT) may be added to oral levodopa to prolong the terminal half-life and increase the area under the levo- dopa concentration–time curve (AUC). It has been hoped that COMT inhibitors would reduce plasma levodopa fluctuations by increasing minimum levodopa concentrations more than maximum levodopa concen- trations (C max ) [2]. Even if such tendencies have been reported [3], it is clear that levodopa concentrations are not significantly more stable with any of the marketed COMT inhibitors entacapone and tolcapone [4–6]. In patients with severe symptom fluctuations, non-oral drug administration is more efficacious, for example intestinal infusion of a levodopa/carbidopa gel [7,8]. Combining levodopa infusion with a COMT inhibitor could lead to better utilization of levodopa during infusion and could allow for dose reduction, which could substantially reduce the cost in patients who use more than one cassette of levodopa/carbidopa intestinal gel (LCIG) daily. However, the combination has never been evaluated, and it is not known how COMT inhibitors affect the smooth plasma levodopa curve achieved by the infusion. Therefore, we designed a Correspondence: D. Nyholm, Department of Neuroscience, Neurology, Uppsala University, SE-75185 Uppsala, Sweden (tel.: +46 18 6115038; fax: +46 18 6115027; e-mail: dag.nyholm@neuro.uu.se). 820 Ó 2011 The Author(s) European Journal of Neurology Ó 2011 EFNS European Journal of Neurology 2012, 19: 820–826 doi:10.1111/j.1468-1331.2011.03614.x