Abstracts

Lacosamide does not alter bone densitometry parameters in juvenile dogs

Abstract number : 2.191
Submission category : 7. Antiepileptic Drugs
Year : 2010
Submission ID : 12785
Source : www.aesnet.org
Presentation date : 12/3/2010 12:00:00 AM
Published date : Dec 2, 2010, 06:00 AM

Authors :
M. Cornet, D. Tytgat and M. L onard

Rationale: Literature suggests that long-term use of antiepileptic drugs (AEDs) such as phenytoin, carbamazepine, sodium valproate or phenobarbital is associated with reduced bone density which may lead to an increased risk of osteoporotic fractures. Studies in growing and young adult animals treated with AEDs have been shown to be good predictors of the human situation and thus support the relevance of animal studies in identifying bone effects. In the present study, the potential effect of lacosamide (LCM), a new AED, on bone quality was assessed in juvenile dogs. Methods: Dogs were treated by the oral route (gelatin capsules) for 33 weeks, and a subset of animals was allowed to recover for 4 weeks. The age of the dogs at start of treatment was 7-8 weeks, which corresponds to a 2-year old child. The dose levels were 0, 3, 10 and 25 mg/kg once daily and 25 mg/kg bid. Due to subsiding signs of toxicity, the 25 mg/kg dose (once daily and bid) was increased to 30 mg/kg from test week 2 onwards and to 35 mg/kg from test day 60 onwards. The right tibia and lumbar vertebrae L3-L4 were subjected to dual energy X-ray absorptiometry (DEXA). Bone mineral content, area and density were calculated by the pDEXA machine software. The analysis of the tibia consisted of four regions of interest: total tibia, proximal and distal 25% of the tibia and midshaft 50% of the tibia. The two lumbar vertebrae were analyzed as one region of interest. Results: After 33 weeks of treatment with LCM up to 70 mg/kg/day (35 mg/kg bid), there were no treatment-related adverse effects on bone mineral content, area or density in either male or female dogs, at either the lumbar vertebrae or any of the 4 regions of interest in the tibia. There were also no treatment-related effects on serum calcium levels, alkaline phosphatase activity or on bone (femur) histopathology. The no observed adverse effect level (NOAEL) in this juvenile dog toxicity study was defined as 10 mg/kg/day based on clinical signs (including tonic convulsions and emesis) observed at 35 and 70 mg/kg/day. Conclusions: LCM daily treatment of juvenile dogs for 33 weeks at doses up to 70 mg/kg/day did not alter bone mineral densitometry parameters. The exposure at this dose level corresponds to clinically relevant exposure levels. The favorable profile of LCM in this juvenile dog study assessing the potential for bone alteration may be one of many key factors to consider when choosing a long-term treatment for epilepsy.
Antiepileptic Drugs