High-dose carbidopa achieves sustained levodopa pharmacokinetics and efficacy in Parkinson's disease models.

Abstract

OBJECTIVES: To evaluate the impact of supraclinical doses of carbidopa on the pharmacokinetics and pharmacodynamics of levodopa in rat and monkey models of Parkinson's disease and to assess the causes for the insufficiency of dihydroxyphenylalanine (DOPA) decarboxylase inhibition at the clinical dose of carbidopa. METHODS: The effects of supraclinical doses of carbidopa and entacapone, a catechol-O-methyltransferase inhibitor, were compared with those of equivalent clinical doses in Parkinson's disease models. Pharmacological assessments were conducted using 6-hydroxydopamine-lesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets. DOPA decarboxylase levels in the human liver, human kidney, and rat liver were quantified. KEY FINDINGS: Supraclinical doses of carbidopa extended the plasma half-life of levodopa in rats, whereas high-dose entacapone did not. Prolonged and sustained pharmacological effects of levodopa were observed in both Parkinson's disease models with supraclinical doses of carbidopa (80-fold and 200-fold greater than the clinical equivalent in rats and marmosets, respectively). DOPA decarboxylase levels in the human liver, human kidney, and rat liver were estimated to be in the submicromolar range, comparable to or exceeding plasma carbidopa concentrations at the clinical dose. CONCLUSION: High-dose carbidopa co-administration is a promising approach to achieve sustained clinical efficacy of levodopa while mitigating the risk of motor complications.