Investigation of a non-steroidal anti-inflammatory drug for oral administration to cattle for the alleviation of pain associated with surgical husbandry procedures

Summary

A group of studies to permit the registration of a novel, non-injectable formulation of meloxicam an non steroidal anti-inflammatory drug to relieve the pain associated with surgical husbandry procedures in cattle. These included:
Study 1: This study aimed to determine the safety of meloxicam at the proposed label dose rate of 0.5 mg/kg bodyweight and at elevated dose rates (3X and 5X the proposed label dose rate) in cattle following oral trans-mucosal (buccal) administration.  Cattle 4 - 6 months of age were used for the study as these are the animals most likely to be treated with the test formulation during routine animal husbandry procedures. Confirmation of the IVPs safety at the label and elevated dose rates was made by comparison of detailed individual clinical examinations and observations; body weight changes; detailed haematological and biochemical parameters; gross pathology following sacrifice and post mortem in all trial cattle, histopathology of selected tissues following sacrifice and post mortem in some trial cattle. No adverse reactions were noted to any of the dose rates tested and no abnormal findings were identified from blood samples or pathology investigations. The study confirmed the safety of the proposed formulation when applied at 1X, 3X and 5X the proposed dose rate of 0.5 mg/kg bodyweight in calves.
Study 2: Bioequivalence studies can be used to demonstrate claims that the new product will have the same target species efficacy and safety as the reference product 1. Determination and comparison of the pharmacokinetic parameters of buccally administered meloxicam with parenterally administered meloxicam was an additional part of the product development process to satisfy product registration requirements. The study was a controlled, blinded, two-sequence, two-period crossover design. Twenty cattle were allocated to 2 treatment groups (two groups of 10).
In Phase 1, cattle in Group 1 received the investigational veterinary product (IVP) Ilium Meloxicam Buccal via oral trans mucosal delivery and cattle in Group 2 received the reference veterinary product (RVP) Metacam 20 mg/mL Solution for Injection via subcutaneous injection.
In Phase 2 the treatments were reversed. Blood samples were collected at predetermined time points prior to and post treatment. Analysis of meloxicam in bovine plasma was performed using a validated liquid chromatography tandem mass spectrometry (LC/MS/MS) method. Sample preparation involved a deproteination step and following addition of an internal standard and extraction into an organic solvent the samples were analysed by LC/MS/MS. Ratios of log-transformed AUC (0-8) for buccal meloxicam vs Metacam SC ranged from 96.7% to 101.2%, with a mean of 99.3%. The 95% confidence interval for the mean ratio ranged from 98.6% to 99.9%, well inside the range suggested by EMEA (European Medicines Agency) guidelines of 80-125% for bioequivalence.
Study 3:  The aim of the study was to investigate the analgesic, anti-inflammatory and antipyretic effects of pre-surgical buccal administration of meloxicam at a dose rate of 0.5 mg meloxicam per kg bodyweight (BW) in calves undergoing surgical castration. The study was a blinded, controlled, randomized block design, incorporating detailed individual behavioural and physiological pain indicators, and assessment of key haematological parameters. Surgical castration was carried out according to the MLA (Meat and Livestock Association) Guide to Best Practice Husbandry in Beef Cattle. Pain related behaviours were assessed every 5 minutes in the first hour post castration.
Subsequently, postural behaviours were classified every 15 minutes for 8 hours post castration and again for 4 hours on the day following castration. Individual rectal temperatures were measured and recorded and individual blood samples were collected at pre-determined time-points. The effect of treatment on the various parameters was analysed statistically and although significant differences were not achieved in all measures there was an overall trend that administration of the investigational veterinary product or the registered veterinary product resulted in mitigation of the physiological and behavioural pain responses demonstrated by surgically castrated calves.