Objective: This series of preclinical studies of novel levodopa and carbidopa/levodopa powder formulations delivered by the POD device to rats and non-human primates (NHP) guided the first dose ranging and pharmacodynamic study in PD patients of a drug-device combination product for treatment of OFF episodes.

Background: Levodopa has been the “platinum” standard PD treatment for > 50 years.1 As PD advances, levodopa benefits become increasingly sensitive to change in systemic concentrations resulting in motor fluctuations (OFF episodes). Literature reports suggest the levodopa plasma concentration increase required to switch from OFF to ON is 200 to 400 ng/mL. Powder formulations of levodopa and carbidopa/levodopa are in development to deliver to the vascular-rich upper nasal cavity with POD technology, allowing self- or caregiver administration, to achieve consistent and rapidly effective treatment to relieve OFF episodes.

Method: Powder levodopa and carbidopa/levodopa formulations were designed and manufactured for POD device delivery and evaluated by analytical methods including HPLC, X-ray diffraction, differential scanning calorimetry, and device compatibility. The PK of lead formulations was evaluated in rat and NHP using species specific POD devices.

Results: Over 50 formulations were manufactured, and 30 formulations were assessed in vivo. PK assessment focused on comparing time to achieve 400 ng/mL plasma levodopa, Tmax, and Cmax. Lead formulation candidates resulted in concentrations of 400 ng/mL within 5-12 min in NHP, a 3 to 5-fold improvement compared to unformulated levodopa. Median Tmax occurred between 30-60 min with Cmax values exceeding 1,000 ng/mL.

Conclusion: POD delivery of optimized novel powder formulations of levodopa and carbidopa/ levodopa resulted in improved PK in preclinical models. This work has led to the selection and further evaluation in a Phase 2A clinical study.

References: 1. LeWitt PA. Levodopa therapy for Parkinson’s Disease: Pharmacokinetics and Pharmacodynamics. Movement Disorders 2015; 30: 64-72. 2. Obeso JA et al. Levodopa motor complications in Parkinson’s disease. Trends in Neuroscience, 2000, 23 (Suppl.): S2-7. 3. Lipp MM et al. Preclinical and clinical assessment of inhaled L-dopa for OFF episodes in Parkinson’s disease. Science Translational Medicine, 2016, 8, 360ra136.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/preclinical-development-of-a-novel-carbidopa-levodopa-precision-olfactory-delivery-pod-drug-device-combination-product-for-the-treatment-of-off-episodes-in-parkinsons-disease/