Objective: To determine the relative bioavailability of levodopa when administered as a subcutaneous (SC) levodopa/carbidopa (LD/CD) infusion with ND0612 versus levodopa derived from oral immediate-release LD/CD (IR-LD/CD) tablets in healthy volunteers.

Background: ND0612 is in development as the first continuous SC LD/CD delivery system for patients with Parkinson’s disease (PD) experiencing motor fluctuations. By avoiding gastrointestinal involvement, ND0612 provides increased bioavailability and reduced variability of LD/CD plasma levels. Several studies have confirmed stable, clinically relevant levodopa plasma levels following ND0612 administration.

Method: This was a single-center, single-dose, open-label, sequence-randomized, 3-period, 2-way crossover pharmacokinetic study in 16 healthy volunteers (11M, 5F; 18-50y). Volunteers were randomized (1:1) to receive either ND0612 infused over 16h (to a total LD/CD dose of 360/45 mg) followed by oral IR-LD/CD 100/25 mg QID over 15h (given every 5h to a total dose of 400/100 mg), or vice versa with an intervening 6-day washout period.

Results: ND0612 SC infusion reached a steady level compared to a fluctuating plasma concentration profile characterized by multiple peaks and troughs observed throughout the day with oral IR-LD/CD given QID due to the relatively short plasma half-life of levodopa. This profile resulted in a 6-fold lower levodopa fluctuation index with ND0612 vs oral IR-LD/CD. Compared with oral IR-LD/CD, levodopa dose-normalized AUCs for ND0612 were approximately 1.3-fold higher.

Conclusion: These PK data confirm that treatment with ND0612 provides a continuous and stable levodopa level, avoiding the peaks and deep troughs associated with oral IR-LD/CD delivery. Levodopa bioavailability (based on dose normalized AUCs) was higher with ND0612 compared to orally administered IR-LD/CD. Therefore, it may be possible to increase the total levodopa dose (from ND0612 and oral) and potentially decrease OFF time in fluctuating PD patients, without increasing troublesome dyskinesia.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/relative-bioavailability-of-levodopa-administered-as-a-subcutaneous-infusion-with-nd0612-versus-oral-immediate-release-levodopa-carbidopa-tablets/