Background: Motor fluctuations are a common complication in Parkinson’s disease (PD) patients on chronic levodopa therapy. Slowed gastric emptying and poor solubility of levodopa (LD) in the gastrointestinal tract may delay onset of drug benefit after dosing. Etilevodopa (EtiLD) is an ethyl-ester prodrug of LD that has greater gastric solubility, passes quickly into the small intestine, is rapidly hydrolyzed to LD, and has a shortened time to maximum LD concentration.

Objective: To determine the efficacy, safety, and tolerability of EtiLD in PD patients with motor fluctuations in a multicenter, randomized, placebo-controlled, double-blind, parallel-groups study.

Methods: PD patients (n = 327) with at least 90 minutes total daily time to “ON” (TTON) after LD dosing were randomized to EtiLD/carbidopa (EtiLD/CD) or LD/carbidopa (LD/CD) for 18 weeks. The primary endpoint was the change from baseline in total daily TTON as measured by home diaries.

Results: The reduction in mean total daily TTON from baseline to treatment was 0.58 hours in the EtiLD/CD group and 0.79 hours in the LD/CD group (p=0.24). There was no significant difference between the EtiLD/CD group compared with the LD/CD group (-6.82% vs -4.69%; p = 0.20) in the reduction of response failures. The total daily OFF time improved in both EtiLD/CD (-0.85 hours) and LD/CD (-0.87 hours) groups without an increase in ON time with troublesome dyskinesias.

Conclusions: Despite the theoretical pharmacokinetic advantage of EtiLD, there was no improvement in TTON, response failures, or OFF time compared with LD.

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