ABSTRACT
BACKGROUND AND OBJECTIVES: Intestinal levodopa/carbidopa gel infusion (LCIG) is superior to oral treatment in advanced Parkinson's disease. The primary objectives of this trial were to investigate if continuous subcutaneous or intravenous infusion with a continuously buffered acidic levodopa/carbidopa solution yields steady state plasma concentrations of levodopa that are equivalent in magnitude, and non-inferior in variability, to those obtained with LCIG in patients with advanced Parkinson's disease. METHODS: A concentrated acidic levodopa/carbidopa (8:1) solution buffered continuously and administered intravenously (DIZ101) or subcutaneously (DIZ102) was compared with an approved intestinal levodopa/carbidopa gel (LCIG) in a randomized, 3-period cross-over, open-label multicenter trial. Formulations were infused for 16h to patients with Parkinson's disease who were using LCIG as their regular treatment. Patients were recruited at several university neurology clinics but came to the same phase I unit for treatment. Pharmacokinetic variables and safety including dermal tolerance are reported. The primary outcomes were bioequivalence and non-inferior variability of DIZ101 and DIZ102 versus LCIG with respect to levodopa plasma concentrations. RESULTS: With dosing adjusted to estimated bioavailability, DIZ101 and DIZ102 produced levodopa plasma levels within standard bioequivalence limits when compared to LCIG in the 18 participants that received all treatments. While the levodopa bioavailability for DIZ102 was complete, it was 80% for LCIG. Therapeutic concentrations of levodopa were reached as quickly with subcutaneous administration of DIZ102 as with LCIG and remained stable throughout the infusions. Due to poor uptake with LCIG, carbidopa levels in plasma were higher with DIZ101 and DIZ102 than with the former. All individuals receiving any of the treatments (n=20) were included in the evaluation of safety and tolerability. Reactions at the infusion sites were mild and transient. DISCUSSION: It is feasible to rapidly achieve high and stable levodopa concentrations by means of continuous buffering of a subcutaneously administered acidic levodopa/carbidopa containing solution. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03419806. Registration first posted 5 Feb 2018, first patient enrolled 16 Feb 2018. Link to registration.
