Objective: To identify the concentration of subcutaneous (SC) carbidopa (CD) that provides optimal bioavailability of a concomitant fixed concentration of levodopa (LD) when administered via SC infusion.

Background: LD is always administered with a dopa-decarboxylase inhibitor such as CD to inhibit its peripheral metabolism and maximize the amount of LD that reaches the brain. ND0612 is a proprietary formulation containing solubilized LD/CD that enables continuous SC infusion for stable LD levels. Although oral dosing of CD is well established, dosing for the SC route requires characterization.

Methods: Two open-label, dose-finding studies were performed to assess the PK of ND0612 formulations with fixed LD concentration (60mg/mL) and varying CD concentrations. The first study in healthy volunteers assessed CD concentrations of 7.5 mg/ml, 6mg/mL, 4mg/mL and the second study assessed CD concentrations of 7.5 mg/ml, and 14 mg/mL in PD patients. Both studies assessed the impact of CD concentration on ‘low dose’ ND0612 (0.24 mL/hr) and ‘high dose’ ND0612 (0.64 ml/hr).

Results: The concentration of SC CD that provides optimal LD levels was confirmed to be 7.5mg/mL. Increasing the CD concentration above this level did not improve the LD bioavailability in either healthy volunteers or PD patients. Lower doses (4 & 6mg/mL) of CD compromised the LD exposure for low dose ND0612.

Conclusions: These two studies demonstrated that the ratio of LD/CD that provides optimal bioavailability of subcutaneous administered levodopa is 8:1. Based on these results the final formulation of ND0612 LD/CD was defined as 60/7.5 mg/mL. With this formulation, steady levodopa levels were consistently maintained within the desired therapeutic range.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/identification-of-the-optimal-carbidopa-concentration-in-subcutaneously-administered-nd0612/