Safety Evaluation of Intranasal Nalmefene in Juvenile Rat Studies in Support of Clinical Trials in Pediatric Patients From Birth to 12 Years of Age.

Abstract

Nalmefene is an opioid antagonist used in OPVEE^® nasal spray approved for use in patients 12 years of age and older. To support future clinical studies in younger pediatric populations, 2 GLP juvenile rat studies were conducted to assess the safety of nalmefene and its associated systemic exposure. Nalmefene was administered daily via intranasal instillation from postnatal day (PND) 7 to PND 28 (corresponding to birth through approximately 3 years) with recovery to PND 91, or from PND 22 to PND 70 (2 years to adolescent) with recovery to PND 114. Exposures on PND 7 were 28-40 times higher than those on PND 28, and exposures on PND 22 were 3-5 times higher than those on PND 70. Exposures on PND 28 were comparable to those on PND 70, attaining adult levels. Considering the extensive metabolism and urinary clearance of nalmefene, these findings are consistent with the maturation of metabolic and urinary clearance pathways during early development. No effects were observed on clinical signs, ophthalmology, food consumption, femur length, sperm parameters, immune responses, or neurodevelopment as assessed by neurohistopathology and neurobehavioral testing for locomotor activity, sensory function, or learning and memory. There were no macroscopic or microscopic findings indicative of target organ, systemic, or neurotoxicity. The NOAELs were 4.25 mg/dose, the highest doses tested. On PND 28, C_max (224 ng/mL) and AUC (311 ng·hr/mL) were 21- and 8-fold higher than those reported in human adults, respectively. The AUC-based safety margins in pediatric patients were estimated to range from 1.5 to 12, depending on the age group (birth-12 years; 3-40 kg).