The pharmacokinetics of continuous subcutaneous levodopa/carbidopa infusion: Findings from the ND0612 clinical development program.

Background

While treatment with levodopa remains the cornerstone of Parkinson's disease (PD) management, chronic oral therapy is often associated with the development of motor complications, that correlate to fluctuating levodopa plasma concentrations, limiting its clinical utility. Continuous infusion is considered to be the optimal delivery route for treating PD patients with motor fluctuations, but current infusion systems require invasive surgery. Subcutaneous infusion of (SC) levodopa has the potential to provide a better tolerated and more convenient route of continuous levodopa delivery. ND0612 is in development as a combination product providing continuous levodopa/carbidopa

Methods

We performed a series of six Phase I and II studies to characterize the pharmacokinetics of levodopa and carbidopa derived from ND0612 infusion with/without adjunct oral therapy of the same ingredients. These studies were conducted in healthy volunteers and in PD patients experiencing motor response fluctuations while on their current levodopa therapy regimen.

Results

Taken together, the results demonstrate dose-proportionality dependent on rate of subcutaneous levodopa infusion leading to stable and sustained plasma concentrations of levodopa. Subcutaneous infusion of ND0612 administered with oral levodopa/carbidopa maintained near-constant, therapeutic levodopa plasma concentrations, thereby avoiding the troughs in levodopa plasma concentrations that are associated with OFF time in PD. The data generated in this series of studies also confirmed that a levodopa/carbidopa dose ratio of 8:1 would be the most reasonable choice for ND0612 development.

Conclusions

This series of clinical pharmacokinetic studies have demonstrated that ND0612, administered continuously with a levodopa concentration of 60 mg/ml combined with carbidopa 7.5 mg/ml, and complemented with oral levodopa/carbidopa, is suitable for 24 h continuous administration in patients with PD. The stable plasma concentrations of levodopa achieved predict utility of ND0612 as a parenteral formulation for achieving clinically useful delivery of levodopa for PD patients.

Informations de copyright

Copyright © 2022 LeWitt, Stocchi, Arkadir, Caraco, Adar, Perlstein, Case and Giladi.

Déclaration de conflit d'intérêts

Author PL reports advisory roles for Abide, Acorda Therapeutics, Adamas, Biogen, Cavion, Denali, Intec Pharma, Jazz Pharmaceuticals, Lundbeck, Neurocrine, Mitsubishi NeuroDerm Ltd., Prexton, Revance, Sage, and US WorldMeds; lecture fees from US WorldMeds, Acorda, American Academy of Neurology, and Kyowa Hakko Kirin. Research grant support from Abide, Acorda, Amneal, Lundbeck, Michael J. Fox Foundation for Parkinson's Research, Mitsubishi NeuroDerm Ltd., Parkinson Study Group; National Institute of Neurological Disorders and Stroke, Pharma 2B, Revance, Hoffmann-La Roche; Sunovion, and Sun Pharma. Author FS reports honoraria and consulting fees from Britannia Pharmaceuticals, GlaxoSmithKline, Boehringer Ingelheim, Lundbeck, Orion, NeuroDerm, Novartis, Teva, Pfizer and Zambon. Authors YC and IP report consultancy for NeuroDerm. Authors LA and RC are employed by NeuroDerm. Author NG serves as consultant to Sionara, NeuroDerm, Pharma2B, Denali, Neuron23 and Abbvie, Sanofi-Genzyme and Biogen. He receives royalties from Lysosomal Therapeutics (LTI) and payment for lectures at Abbvie, Sanofi-Genzyme and Movement Disorder Society. He received research support from the Michael J. Fox Foundation, the National Parkinson Foundation, the European Union and the Israel Science Foundation as well as from Teva NNE program, Biogen and Ionis. He receives support from the Sieratzki Family Foundation and the Aufzien Academic Center in Tel-Aviv University. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.