Safety of an amino-acetonitrile derivative ( AAD ), monepantel, in weaned lambs following repeated oral administration.
OBJECTIVE
To demonstrate the safety in weaned lambs of repetitive oral doses of monepantel, an amino-acetonitrile derivative (AAD), when administered at the proposed maximum recommended dose (MRD) and three and five times the MRD over 24 weeks.


METHODS
A randomised controlled blinded study design was used. Fifty-six weaned lambs were randomly allocated into a control group, the MRD (3.75 mg/kg) and three (11.25 mg/ kg) and five (18.75 mg/kg) times the MRD treatment groups (n=7 castrated males plus seven females each). Treatment doses of monepantel were calculated based on the MRD of 3.75 mg/ kg, and administered orally on eight occasions at intervals of approximately 21 days. Detailed recording at multiple time points were made of veterinary examinations, observations for adverse events, bodyweight measurements, faecal scores, and haematology, clinical chemistry and coagulation variables. Gross pathology (including measurement of organ weights) and histopathology were performed at the completion of the study.


RESULTS
All lambs treated with monepantel and those in the control group thrived, grew and behaved normally to the end of the study. No treatment-related, toxicologically relevant adverse events, clinical observations or macroscopic or microscopic changes were observed. Furthermore, there were no significant differences in bodyweight or organ weights, and haematological, clinical chemistry or coagulation variables between lambs treated with monepantel and control lambs.


CONCLUSIONS
Repeated oral administration of monepantel at the MRD and three and five times the MRD every 3 weeks for eight treatments was not associated with any treatment-related adverse effects and was systemically very well tolerated in weaned, growing lambs. This study demonstrated that this population of lambs could tolerate accidental overdoses of up to five times the MRD of monepantel or prolonged repetitive administration at recommended doses or overdoses.
Malikides
N
N
Novartis Animal Health Australasia Pty Limited, Yarrandoo R&D Centre, 245 Western Road, Kemps Creek, New South Wales 2178, Australia. nick.malikides@novartis.com
Helbig
R
R
Roth
D R
DR
Alexander
A
A
Hosking
B C
BC
Strehlau
G A
GA
D000284:Administration, Oral; D000607:Aminoacetonitrile / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D000831:Animals, Newborn; D000871:Anthelmintics / Q000009:adverse effects* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D011897:Random Allocation; D012449:Safety; D012756:Sheep; D012757:Sheep Diseases / Q000188:drug therapy*; D016896:Treatment Outcome
D000871:Anthelmintics; D000607:Aminoacetonitrile; C533978:monepantel