Safety of an amino-acetonitrile derivative (AAD), monepantel, in weaned lambs following repeated oral administration

Abstract

AIM: 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 AND CLINICAL RELEVANCE: 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.

KEY WORDS:

• Lambs
• amino-acetonitrile derivative
• monepantel
• overdose
• target animal safety
• adverse event
• toxicology
• anthelmintic

Acknowledgements

Assistance with the implementation of this study by the staff of Novartis Animal Health Australasia Pty Limited, Yarrandoo R&D Centre, Australia, is gratefully acknowledged. The authors also wish to thank Julie Boisclair, Catherine Boeglen, Anne Provencher- Bolliger, Lynda Nolan and Barbara Greutmann from Novartis Pharma AG, Basel, Switzerland, for their tireless advice and help with the clinical pathology and pathological components of this study. Thanks also go to Robert Cody, Ronald Kaminsky and Arthur Redpath for reviewing this paper. Finally, Alan Alexander was affiliated with Novartis Animal Health at the time of writing this manuscript.