A phase I study to evaluate the effect of high-dose carbidopa on levodopa pharmacokinetics.

Levodopa is the gold standard treatment for Parkinson's disease. However, a high unmet medical need exists for longer-lasting oral levodopa formulations to achieve sustained motor improvement with reduced risk of the effect wearing off. In our previous non-clinical studies using rats, more than 3-fold prolongation of the levodopa half-life was achieved when it was combined with a high carbidopa dose. This study aimed to evaluate the effects of high-dose carbidopa on the pharmacokinetics of levodopa. A phase I study was performed to examine the effects of a combination of levodopa, carbidopa, and entacapone in healthy male volunteers. Levodopa and entacapone doses were set at approved dose levels. The carbidopa dose ranged from the approved 10 mg-600 mg. In addition to plasma concentrations of levodopa, those of the metabolites were also determined to evaluate their inhibitory effects on levodopa-metabolizing enzymes. The plasma concentrations of levodopa and its metabolites were monitored by liquid chromatography-tandem mass spectrometry up to 24 h after administration. The observed adverse effects were mild, and all participants completed the study. At higher carbidopa doses, the area under the levodopa plasma concentration-time curve increased by approximately 2-fold, and the half-life of levodopa was slightly prolonged by < 1.4-fold. These changes were much smaller than those observed in rats. The ratios of levodopa metabolites suggested that dopa deoxycarboxylase inhibition was saturated at a carbidopa dose of 300 mg. In conclusion, higher carbidopa doses are tolerable, and the effect of carbidopa on levodopa half-life is limited. Clinical trial registration: https://jrct.mhlw.go.jp/en-latest-detail/jRCT2051200104, registry number jRCT2051200104.