Ever since its early clinical use in the 1960s, levodopa has remained the gold standard of symptomatic efficacy in the drug treatment of Parkinson's disease (PD). Motor response fluctuations and drug-induced dyskinesias seriously compromise the unparalleled symptomatic efficacy of l-dopa during long-term treatment. Discontinuous drug delivery resulting from the short half-life of l-dopa and erratic gastrointestinal absorption plays a major role in the pathophysiology of these motor complications. Several approaches to improve the pharmacokinetics and ways of administration of l-dopa are in different stages of clinical development and include novel formulations as well as nonoral routes of drug delivery. IPX066 is a novel extended-release l-dopa capsule that has successfully completed phase III clinical trials while the l-dopa prodrug XP21279 and a gastric retention formulation ("accordion pill") are in earlier phases of clinical development. Novel enzyme inhibitors enhancing l-dopa efficacy and half-life are also still being developed, including a novel catechol-O-methyltransferase inhibitor with once-daily pharmacokinetics, and there are studies testing the effects of increasing the dose of amino acid decarboxylase inhibitors given concomitantly with l-dopa. Intrajejunal infusion of a gel formulation of l-dopa/carbidopa is in clinical use in Europe, and its efficacy to smooth out motor fluctuations has recently been shown in a randomized, controlled trial. Subcutaneous and intrapulmonal delivery routes of l-dopa have reached phase III of clinical development. After more than 50 years of clinical use, l-dopa not only remains the gold standard of symptomatic efficacy, but it also remains a drug in active clinical development.
Keywords: COMT inhibitors; extended-release formulation; intrapulmonary delivery; levodopa infusions; levodopa microtablets.
© 2014 International Parkinson and Movement Disorder Society.