XP-21279

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 ofl‐dopa during long‐term treatment. Discontinuous drug delivery resulting from the short half‐life ofl‐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 ofl‐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‐releasel‐dopa capsule that has successfully completed phase III clinical trials while thel‐dopa prodrug XP21279 and a gastric retention formulation (“accordion pill”) are in earlier phases of clinical development. Novel enzyme inhibitors enhancingl‐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 withl‐dopa. Intrajejunal infusion of a gel formulation ofl‐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 ofl‐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. © 2014 International Parkinson and Movement Disorder Society

The objective of this study was to assess the efficacy, safety, and pharmacokinetics of XP21279‐carbidopa in patients with Parkinson's disease who experience motor fluctuations compared with immediate‐release carbidopa‐levodopa tablets. XP21279 is a levodopa prodrug that is actively absorbed by high‐capacity nutrient transporters expressed throughout the gastrointestinal tract and then rapidly converted to levodopa by carboxylesterases. XP21279‐carbidopa sustained‐release bilayer tablets were developed to overcome pharmacokinetic limitations of levodopa by providing more continuous exposure. Patients with motor fluctuations who required carbidopa‐levodopa four or five times daily were optimized for 2 weeks each on carbidopa‐levodopa four or five times daily and XP21279‐carbidopa three times daily in a randomized sequence. Next, they received each optimized treatment for 2 weeks in a double‐blind/double‐dummy, randomized sequence. The primary outcome measure was change from baseline in daily off time at the end of each double‐blind treatment period. All patients at 2 sites underwent pharmacokinetic analyses. Twenty‐eight of 35 enrolled patients completed both double‐blind treatments. The mean total daily off time was reduced from baseline by a mean (± standard error) of 2.7 hours (± 0.48 hours) for immediate‐release carbidopa‐levodopa and 3.0 hours (± 0.57 hours) for XP21279‐carbidopa (P = 0.49). Among 11 patients who completed pharmacokinetic sampling on each optimized treatment, the percentage deviation from the mean levodopa concentration was lower (P < 0.05) for XP21279‐carbidopa than carbidopa‐levodopa. Both treatments had a similar incidence of new or worsening dyskinesias. XP21279‐carbidopa administered three times daily produced a reduction in off time similar to that of carbidopa‐levodopa administered four or five times daily, and the difference was not statistically significant. XP21279‐carbidopa significantly reduced variability in levodopa concentrations compared with carbidopa‐levodopa. © 2013 International Parkinson and Movement Disorder Society