Regulatory thresholds for xylazine – review and analysis based on recent pharmacokinetic data

Xylazine is an α2-adrenergic receptor agonist and a short acting sedative/analgesic widely used in equine practice since its original approval by the FDA in 1988. Closely related agents include Detomidine, Metdetomidine, Romifidene, Amitraz and Guanabenz. Xylazine is the shortest acting member of this group and is a Racing Medication and Testing Consortium (RMTC) “Controlled Therapeutic Medication” (version 2.2). In 2013 the RMTC interim threshold for xylazine was set at 10pg/ml plasma with a 48-hour withdrawal and no defined dose. Application of this regulatory threshold in Washington State led rapidly to an apparent therapeutic average of about 75pg/ml following a 200mg dose IV at 54 hours prior to post. Based on Toutain's reported Irrelevant Plasma Concentration (IPC) for xylazine [2013] and the very short duration of action of xylazine, an interim 300pg/ml regulatory threshold for xylazine was proposed. Soon thereafter published pharmacokinetic data for xylazine up to 12 hours post-administration showed that the terminal elimination of xylazine slows markedly from 6 hours post-administration, leading to a flat terminal half-life. The regulatory outcome of this slow terminal elimination curve for xylazine is that it can be detected in plasma for hours to days beyond any pharmacologic effect of the drug. Based on these considerations, the regulatory threshold for xylazine in Washington State was adjusted upwards to 200pg/ml on an interim basis. Following this adjustment, review of reported plasma concentrations of xylazine in Washington State post-race samples suggests that this 200pg/ml in plasma adjusted interim regulatory threshold is likely a more appropriate and clinically relevant 48-hour post-administration regulatory threshold for xylazine. This 200pg/ml plasma regulatory threshold was soon adopted by the RMTC and is currently well supported by published research and practical regulatory experience.