Pharmacokinetics of Intravenously (DIZ101), Subcutaneously (DIZ102), and Intestinally (LCIG) Infused Levodopa in Advanced Parkinson Disease

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.

Effective Management of “OFF” Episodes in Parkinson’s Disease: Emerging Treatment Strategies and Unmet Clinical Needs

“… 110 Successful subcutaneous solutions require high aqueous solubility and excellent chemical stability. 111 While ND0612 achieves a highly concentrated CD/LD solution, its alkaline pH causes a high rate of skin nodules – around 95% of people receiving ND0612. 112 ABBV-951 is a phosphate prodrug of CD/LD that appears more stable and is at a near neutral pH, thus avoiding excessive skin irritation.…”

“… 113 Lastly, Dizlin pharmaceuticals is currently developing DZ102, which consists of a stock solution (CD/LD dissolved at a low pH) and a buffer that brings the solution to a physiologically favorable pH when mixed. 111 The stock solution is stable at room temperature for >3 months and the buffered mixture allows for better skin tolerability. 111 …”

“… 111 The stock solution is stable at room temperature for >3 months and the buffered mixture allows for better skin tolerability. 111 …”

“…114 DIZ102 was found to be non-inferior to LCIG in regards to fluctuations of levodopa plasma levels, a property which is essential for infusions. 111 If approved, these investigational products may provide a less invasive and better tolerated alternative to infusion therapies, especially in older patients in whom DBS is not an option and a PEG-J procedure may be less desired.…”

Will Subcutaneous Levodopa Stick?

“…[6][7][8] In this issue of Neurology ® , Bergquist et al present pharmacokinetic and preliminary safety data of a new formulation of carbidopa/levodopa (DIZ102). 9 This is a highly concentrated solution of carbidopa/levodopa at acidic pH (to improve solubility and prevent oxidation) that is delivered by subcutaneous infusion. Before administration, the acidic solution must be mixed with a buffer to create a solution of neutral pH.…”