20-Week toxicity study of rotigotine behenate extended-release microspheres for intramuscular injection in sprague...

Based on the concept of continuous dopaminergic stimulation (CDS), Rotigotine Behenate extended-release microspheres for injection (RBEM) are currently under development. To support human clinical trials of RBEM, a 20-week repeat-dose toxicity study was conducted. SD rats intramuscularly received RBEM (60, 180, and 540 mg/kg) once every 4 weeks for 5 repeated doses followed by a 12-week recovery period, no clear sex difference was noted in the plasma exposure of rotigotine in rats, and the exposure generally increased in a dose-proportional manner. No obvious systemic toxicity occurred. Ovarian corpus luteum and breast acinar hypertrophy in rats were believed to be associated with the activation of dopamine receptors by RBEM and decreased prolactin levels. The reversible vacuolar degeneration or foamy macrophage infiltration at the injection site, adjacent tissues, and alveoli of rats were associated with local inflammation and foreign body removal reaction caused by PLGA and SCMC. In this study, the non-observed-adverse-effect-level (NOAEL) in rats was 540 mg/kg (based on rotigotine), which was equivalent to 24 times the maximum clinical recommended dose of RBEM, 448 mg/person/28 days (expressed as the dose of rotigotine behenate). In conclusion, RBEM exhibited a good safety margin and can be used in phase I clinical trials. Keywords: Parkinson's disease; RBEM; Continuous dopaminergic stimulation; Repeated dose toxicity.