Pharmacodynamics, safety pharmacology and local tolerance of rotigotine behenate extended-release microspheres

Continuous dopaminergic stimulation (CDS) is a key strategy in Parkinson's disease (PD) treatment. We developed Rotigotine Behenate Extended-Release Microspheres (RBEM), an injectable 28-day sustained-release formulation that hydrolyzes in vivo to release active rotigotine, maintaining therapeutic levels. RBEM shows improved PK profiles-longer duration and more stable drug concentrations-versus existing CDS therapies. Its monthly dosing also enhances patient compliance, potentially optimizing efficacy and safety. Thus RBEM represents a promising advance in CDS for PD. A comprehensive preclinical assessment of RBEM was conducted to support clinical trial initiation. Gi Cell-based functional assay demonstrated that Rotigotine (active metabolite) showed potent agonism at dopamine D₃ (EC₅₀ = 0.53 nM), D_2S (11.6 nM), and D_2L (21 nM) receptors. Its prodrug, rotigotine behenate, exhibited selective D_2S agonism (EC₅₀ = 42 nM). Electrophysiological assessment using manual patch clamp technique revealed that RBEM showed weak hERG inhibition (IC₅₀ = 0.12 μM) but no cardiotoxicity in 20-week primate studies. Whole-body plethysmography studies demonstrated that dose-dependent increases in respiratory rate/min volume were observed in rats (180–540 mg/kg), but not in primates. No significant CNS effects (FOB assay, SD rats) or hemolysis (rabbit erythrocytes, ≤ 227 mg/mL). Intramuscular injection caused reversible irritation attributable to PLGA excipient, consistent with marketed microsphere formulations.

In summary, RBEM's pharmacological activity is mediated by rotigotine release, with a favorable preclinical safety profile supporting clinical development. Respiratory, cardiovascular, and injection-site reactions should be prioritized in clinical monitoring.