ABSTRACT
Continuous dopaminergic stimulation (CDS) has become an important strategy for the development of drugs to treat Parkinson's disease (PD). Rotigotine behenate extended-release microspheres (RBEM) for injection represents a new treatment regime for CDS and is being applied for clinical trial. Our study in cynomolgus monkeys was a 20-week repeat dose toxicity investigation with RBEM at dosages of 90, 180, 360, with a 12-week recovery period. The results observed some irritations in the application site and surrounding tissues in Placebo microspheres and each dose of RBEM, was accompanied with increased white blood count and fibrinogen. RBEM-treated monkeys were additionally noted with a pharmacological action-related decrease in prolactin. These findings showed certain reversibility after the 12-week recovery phase. No clear sex difference was noted in the plasma exposure to rotigotine. The exposure generally increased in a dose-proportional manner. In summary, major toxicological effects are associated with the dopamine agonist-related properties of rotigotine, and the removal of foreign bodies caused by p oly (lactide-co-glycolide) (PLGA)and sodium carboxymethyl cellulose (SCMC), and the no-observed-adverse-effect-level (NOAEL) was 360 mg/kg.
Subject(s)
Microspheres , Tetrahydronaphthalenes , Thiophenes , Animals , Female , Male , Delayed-Action Preparations , Dopamine Agonists/toxicity , Dopamine Agonists/administration & dosage , Dose-Response Relationship, Drug , Injections, Intramuscular , Macaca fascicularis , Tetrahydronaphthalenes/toxicity , Tetrahydronaphthalenes/administration & dosage , Thiophenes/toxicity , Thiophenes/administration & dosageABSTRACT
Continuous dopaminergic stimulation (CDS) has become an important strategy for the development of drugs to treat Parkinson's disease (PD). Rotigotine behenate extended-release microspheres (RBEM) for injection represent a new treatment regime for CDS and are undergoing clinical trials. In this study, we aimed to investigate the effect of RBEM on genotoxicity, fertility and early embryonic development. We used the Ames test, Chinese hamster lung (CHL) cell chromosome aberration test and the mouse bone marrow micronucleus test, to evaluate the genotoxicity of RBEM. These tests were all negative, thus indicating that RBEM did not induce genotoxicity. In reproduction toxicity testing in male rats on obvious findings following intramuscular administration (i.m.) of RBEM at up to 540 mg/kg (P > 0.5), when female rats were administered with RBEM in the dose range of 60 to 540 mg/kg given (i.m.), there were clear effects on fertility and early embryonic development. These results indicated that RBEM could induce toxicity in female rats and exert effect on fertility and early embryonic development stage.