Three-month subchronic intramuscular toxicity study of rotigotine-loaded microspheres in Cynomolgus monkeys

Continuous dopaminergic stimulation (CDS) is an important drug development strategy in the treatment of Parkinson’s disease (PD). Rotigotine is a non-ergoline D3/D2/D1 dopamine receptor agonist for treating PD. As a new treatment option for CDS, rotigotine-loaded microspheres (RoMS), long-acting sustained-release microspheres with poly(lactide-co-glycolide) as drug carrier, are now being evaluated in clinical trial. In the present study, the subchronic toxicity in Cynomolgus monkeys has been characterized via intramuscular administration with RoMS at 0, 10, 40 and 160 mg/kg, weekly for 3 months with a 1-month recovery period. The NOAEL was 10 mg/kg/week. One male at 160 mg/kg died from an extensive pulmonary embolism. The major toxicological effects were associated with dopamine agonist-related pharmacodynamic properties of rotigotine (e.g., hyperactivity and stereotype, decreased serum prolactin level) and foreign body removal reaction induced by poly(lactide-co-glycolide) and carboxymethycellulose sodium (e.g., increased mononuclear cells and neutrophils, thymus atrophy and vacuolar degeneration of adrenal cortex, foreign body granuloma with foam cells accumulation at injection sites and foam cells accumulation in spleen and multiple lymph sinuses). At the end of recovery period, above findings recovered to a normal level or to a certain degree except vacuolar degeneration of adrenal gland. RoMS has exhibited high safety on monkeys.

► Rotigotine-loaded microspheres (RoMS) is a long-acting sustained-release formulation.
► Subchronic toxicity of RoMS in Cynomolgus monkeys has been evaluated.
► The No Observed Adverse Effect Level (NOAEL) was 10 mg/kg/week.
► Major toxicological effects were related to dopamine receptor activation by rotigotine.
► Foreign body removal reaction was induced by PLGA and SCMC.