Abstracts

Rationale: Lacosamide is a functionalized amino acid which showed anticonvulsant as well as analgesic effects in a large variety of animal models and is currently being evaluated in Phase 3 clinical trials. The objective of the present experiments was to assess its safety profile in preclinical reproductive, developmental and juvenile toxicity studies.Methods: Lacosamide was tested for effects on all stages of reproduction (fertility, early and embryo-fetal development and pre-/postnatal development including maternal function) by oral administration of up to 200 or 25 mg/kg/day to rats or rabbits, respectively. Further, juvenile rats were treated orally with lacosamide up to 180 mg/kg/day for 6 weeks starting on post-natal day 7 followed by a 4-week recovery period and mating within a previously treated subgroup. In addition, juvenile dogs were treated orally with lacosamide up to 25 mg/kg/day for 6 weeks starting at the age of 8 weeks (after weaning).Results: Developmental toxicity was observed at a maternally toxic dose, but there was no evidence of adverse effects on male or female reproductive function or teratogenicity. In the juvenile animals, in principle the same effects as in chronic toxicity studies with adult animals were noted, i.e. there was no indication of age-specific toxicity. The juvenile animals appeared to be slightly less affected than adults. In rats, body weight reduction was dose-limiting and, as a secondary effect to this, a slightly delayed development of the high dose groups in general was observed. Importantly, no treatment-related adverse effects were noted on the developing rat brain neither on the histomorphological nor functional level.Conclusions: Lacosamide showed a favorable profile in preclinical reproductive, developmental and juvenile toxicity studies.