"Dose failures" and "delayed on" phenomena following an intake of
levodopa dose in patients with
Parkinson's disease (PD) with motor fluctuations may be caused by stagnation of poorly soluble
levodopa in the atonic stomach.
Etilevodopa is a unique, highly soluble
prodrug of
levodopa. When ingested,
etilevodopa is more readily dissolved in the stomach than
levodopa. It passes unchanged through the stomach to the duodenum, where it is rapidly hydrolyzed by local
esterases and rapidly absorbed as
levodopa. To compare the pharmacokinetics of three different modes of
etilevodopa/
carbidopa administration with standard
levodopa/
carbidopa tablets in fluctuating PD patients, 29 patients with PD and response fluctuations were enrolled in an open-label, randomized, four-way crossover study of single doses of 4 treatments: swallowed
etilevodopa/
carbidopa tablets,
etilevodopa/
carbidopa tablets dissolved in water,
etilevodopa oral
solution with
carbidopa tablets, and standard
levodopa/
carbidopa tablets. To measure the maximal concentration (Cmax), time to Cmax (tmax), and area under the curve (AUC) of plasma
levodopa,
etilevodopa, and
carbidopa, blood samples were drawn before
drug administration and at intervals up to 240 minutes thereafter. Plasma
levodopa tmax was significantly shorter with all three modes of administration of
etilevodopa (mean of about 30 minutes) than with
levodopa treatment (mean of 54 minutes). During the first 45 minutes after
drug ingestion, plasma
levodopa AUC was significantly greater after
etilevodopa administration than after
levodopa administration.
Levodopa AUC for 0 to 1 hour and 0 to 2 hours were also significantly greater following administration of
etilevodopa/
carbidopa swallowed
tablets than following administration of
levodopa/
carbidopa tablets. Mean
levodopa Cmax was in the range 2.3 to 2.7 microg/mL for all treatments.
Levodopa Cmax was significantly greater following treatment with
etilevodopa swallowed
tablets than with
levodopa tablets.
Etilevodopa/
carbidopa was well tolerated, with a safety profile comparable to that of
levodopa/
carbidopa. The shorter
levodopa tmax observed with
etilevodopa potentially translates to a shorter time to "on". Clinical trials with
etilevodopa/
carbidopa tablets should be carried out in PD patients with response fluctuations such as "delayed on" and "dose failures".