Reproductive safety of an amino-acetonitrile derivative (AAD), monepantel, in rams following repeated oral administration

Abstract

AIM: To demonstrate the clinical and reproductive safety in rams of repetitive oral doses of monepantel, an amino-acetonitrile derivative (AAD), when administered at three times the proposed maximum recommended dose (MRD) over an entire spermatogenic cycle and during mating with ewes.

METHODS: A randomised controlled blinded study design was used with 28 rams randomly divided into two groups. The control group was treated with saline, and the other group was given three times the MRD (11.25 mg/kg) of monepantel. Treatments were administered orally every 5 days, for 100 days, during an entire spermatogenic cycle and subsequent mating period. Detailed recording at multiple time points were made of veterinary examinations; observations for adverse events; bodyweight measurements; faecal scores; haematology, clinical chemistry and coagulation variables; semen indices; evaluation of serving capacity; and gross pathology (including measurement of organ weights) performed on 10 rams from each group at the completion of the study.

RESULTS: All rams treated with monepantel and those in the control group thrived and behaved normally to the end of the study. No treatment-related, toxicologically relevant adverse events, clinical observations or macroscopic changes were observed. Furthermore, there were no significant differences in bodyweight or organ weights, and haematological, clinical chemistry or coagulation variables between rams treated with monepantel and control rams. No significant changes were observed in any semen variable measured in any rams, and the serving capacity of rams mated to ewes was unaffected.

CONCLUSIONS AND CLINICAL RELEVANCE: Repeated oral administration of monepantel at three times the MRD every 5 days over an entire spermatogenic cycle and during mating was not associated with any treatment-related adverse effects on the reproductive performance of rams and was systemically very well tolerated. This study demonstrated that this population of rams could tolerate accidental overdoses of up to three times the MRD of monepantel or prolonged repetitive administration at overdoses. Thus, those so treated entering a breeding programme would have normal sperm indices, mating behaviour, and health.

KEY WORDS:

• Rams
• amino-acetonitrile derivative
• monepantel
• overdose
• target animal safety
• adverse event
• reproduction
• 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, Barry Hosking and Arthur Redpath of Novartis Animal Health for reviewing this paper.