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100 pg/ml, based on a single intra-articular dose of 9 mg TCA (Knych et al. 2013) and 100 mg MPA (Knych et al. 2014). The corresponding withdrawal time guidance is 7 and 21 days for TCA and MPA, respectively. For betamethasone, the regulatory threshold concentration and withdrawal time guidance is 10 pg/ml and 7 days, respectively based on a single intra-articular dose of 9 mg (Anon 2014). For isoflupredone acetate (IPA), a regulatory threshold concentration of 100 pg/ml, with a withdrawal time guidance of 7 days, is recommended (Benson et al. 2014). These recommended regulatory thresholds were established based on practical horseracing and racehorse management and not necessarily based on pharmacodynamic or therapeutic considerations. Since the withdrawal time guidance for each drug was based on single dose studies and in the majority of cases practitioners use combination corticosteroid therapy, widely varying doses and treat multiple joints to most effectively treat their patients, the goal of the study described here was to assess the applicability of the ARCI regulatory guidance for each corticosteroid following intra-articular (IA) administration of various clinical protocols employed by racecourse practitioners.
Materials and methods
Horse selection Fifty-eight Thoroughbred (TB) and 82 Quarter Horse (QH) racehorses were studied. Horse selection as well as the specific corticosteroid, doses administered and joints to be treated were determined by the treating practitioner as part of their clinical evaluation of each animal. For the TB portion of the study, 18 horses received TCA (Vetalog; Kenalog)1,2, (maximum cumulative dose of 9–18 mg), 21 horses received MPA (Depo-Medrol)3 (maximum cumulative dose of 40– 600 mg), 7 horses received IPA (Predef 2X)3 (maximum cumulative dose of 4–18 mg) and 12 horses received betamethasone (Celestone; Betamethasone Sodium Phosphate and Betamethasone Acetate)4,5, (maximum cumulative dose of 12–60 mg) IA in various joints. Quarter Horses received varying combinations of corticosteroids IA into various joints including: 1) betamethasone (12–24 mg), 2) IPA (4–26 mg) + betamethasone (12–42 mg), 3) MPA (40 mg) + betamethasone (24 mg), 4) TCA (10–20 mg) + betamethasone (6–12 mg), 5) TCA (10-24 mg) + IPA (2- 20 mg) + betamethasone (6–36 mg), 6) MPA (20–40 mg) + IPA (5-30 mg) + TCA (10–40 mg) + betamethasone (6– 30 mg), 7) TCA (2–20 mg) + MPA (20–40 mg) + IPA (8– 25 mg) and 8) TCA (20–40 mg) + MPA (20–40 mg) + betamethasone (18–30 mg). Details regarding the specific drug administered, manufacturer, dose, joints treated, dose time, concurrent IA administration of other compounds as well as treatment with IA or intramuscular (i.m.) corticosteroids in the preceding 30 or 60 days, respectively were recorded. All drug administrations were conducted by the treating practitioner. Blood samples were collected by direct venipuncture at
0, 7, 10, 14, 21, 28 and 35 (MPA only) days post drug administration from TBs and 0, 7 and 10 days post administration from QH. All samples were collected by the treating practitioner into serum separator tubes6. Sample collection, storage at the racetrack and shipping procedures were comparable to the processes for post race sample collection. Samples were centrifuged at the racetrack at
3300 revolutions/min (RPM) and refrigerated prior to being shipped to the laboratory. Upon receipt at the laboratory, samples were centrifuged again at 3000 RPM for 10 min and serum immediately transferred into storage cryovials.7 All
samples were stored at 20°C (approximately 2 weeks) until analysed by tandem liquid chromatography mass spectrometry (LC-MS/MS) for quantitation of serum methylprednisolone (MP), TCA, isoflupredone (IP) and betamethasone concentrations using previously validated assays used for post race drug testing (Knych et al. 2013, 2014, 2015).
Results
Thoroughbred study Of the 58 TBs included in the study, 6 received MPA, 3 received isoflupredone and one received TCA IA within 30 days prior to enrolment in the study. Of these, only one horse that had received MPA had a baseline concentration (520 pg/ml) exceeding the regulatory threshold. Three horses received TCA and 3 horses received MPA as an i.m. injection within 60 days of commencement of the study. Serum baseline concentrations were below the regulatory threshold for all 3 horses. Table 1 lists the time at which serum concentrations of TCA, MP, IP and betamethasone fell below the ARCI regulatory threshold in the TB horses. The elimination time varied based on the maximum dose administered, specific joints injected as well as the total number of joints treated. Methylprednisolone acetate concentrations were below the regulatory threshold concentration in all horses by Day 21 post administration. Serum concentrations fell below the ARCI regulatory threshold by Day 7 (100 pg/ml) for both TCA (9–18 mg dose) and IPA (4– 18 mg dose). For betamethasone, 7 of 10 horses had serum concentrations below the regulatory threshold (10 pg/ml) by 7 days post administration. Serum betamethasone concentrations in the remaining 3 horses fell below the regulatory threshold by Day 10 post drug administration. Concurrently administered IA medications included hyaluronic acid (HA) (17 horses) and a HA, sodium chondroitin sulfate and N-acetyl-D-glucosamine combination product (Polyglycan)8 (7 horses) (Table 2). Of the 3 horses in which betamethasone concentrations exceeded the regulatory regulatory threshold at 7 days post administration, one had received 30 mg and 2 had received 60 mg of betamethasone. All 3 horses also received IA Polyglycan (2.5–5 ml) concurrent with betamethasone administration (Table 2).
Quarter Horse study Of the 82 QHs studied, 57 received MPA, 2 received betamethasone, 2 received TCA and one received IPA IA within 30 days of commencement of the study. Nineteen of the 57 that received an IA MPA injection in the previous 30 days had serum MP concentrations at or above the regulatory threshold (100 pg/ml). No TCA or IP was detected in baseline samples from horses reported as receiving either drug in the preceding 30 days. A total of 13 horses received an i.m. injection of either MPA (10 horses), TCA (2 horses) or IPA (one horse) within 60 days prior to enrolment in the study. Of these horses, 5 had MP serum concentrations that were ≥100 ng/ml in baseline samples with 4 of these animals also having received an IA injection of MPA within the preceding 30 days. The time at which concentrations fell below the ARCI regulatory threshold for combination IA corticosteroid
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