Is intranasal administration an opportunity for direct brain delivery of lacosamide?

Lacosamide is well-known as an effective and safe anticonvulsant drug. Nevertheless, there is also evidence of anti-epileptogenic, neuroprotective and antinociceptive properties of lacosamide. It is currently available as oral and intravenous (IV) formulations, and its brain concentrations and therapeutic effects depend on its passage across the blood-brain barrier (BBB). Therefore, to circumvent the restrictive BBB, we herein evaluated the intranasal (IN) administration of lacosamide. Nasal thermoreversible gels were screened in vitro for their influence on the viability of human nasal septum (RPMI 2650) and lung adenocarcinoma (Calu-3) cells. According to the Alamar Blue test, the in situ gel composed of Pluronic F-127 (22.5%, w/v) and Carbopol 974P (0.2%, w/v) did not affect cell viability, which remained higher than 85%, within the concentration range of lacosamide. The in situ gel was intranasally administered to healthy male CD-1 mice (8.33 mg/kg) to describe the pharmacokinetic profiles of lacosamide in plasma, brain, lung and kidney and compare them with those obtained after IV administration of the same dose. Accordingly, IN administration allowed a fast (t in plasma: 5 min) and complete systemic absorption of lacosamide (absolute bioavailability: 120.46%). Interestingly, IN lacosamide demonstrated higher exposure (given by the AUC) in the brain (425.44 µg.min/mL versus 274.49 µg.min/mL), but lower exposure in kidneys (357.56 µg.min/mL versus 762.61 µg.min/mL), in comparison to IV administration. These findings, together with the t in brain of 15 min, a drug targeting efficiency (DTE) of 128.67% and a direct transport percentage of 22.28%, evidence that part of lacosamide reaches the brain directly after nasal administration, even though penetration into the brain from the systemic circulation seems to be the major determinant of brain exposure. Importantly, lacosamide concentrations found in lungs following IN administration were considerably higher than those observed after IV injection, until 30 min post-dosing (p < 0.05). Nevertheless, attained drug concentrations were lower than those tested in vitro in the Calu-3 cell line (1-100 µM), indicating that adverse effects are unlikely to occur in vivo. Hence, it seems that the proposed IN route has potential to be a suitable and valuable strategy for the brain delivery of lacosamide in emergency conditions and for the chronic treatment of epilepsy and other neurological diseases.