Levodopa infusion combined with entacapone or tolcapone in Parkinson disease: a pilot trial

Background and purpose: Catechol‐O‐methyltransferase inhibitors may be used to decrease levodopa requirement. The objective was to investigate whether the levodopa/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/carbidopa/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‐methyltransferase inhibitors administered in 5‐h intervals may be useful in cases where levodopa/carbidopa intestinal gel dose reduction is wanted. Stability of plasma levodopa 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.