Testing for therapeutic medications: analytical/pharmacological relationships and 'limitations' on the sensitivity of testing for certain agents

Abstract

Proper veterinary care of horses requires that horses in training have access to modern therapeutic medication. However, the sensitivity of equine drug testing now allows for detection of pharmacologically insignificant concentrations of many therapeutic medications. In 1995, the Association of Racing Commissioners International (ARCI) resolved that members 'address trace level detection so as not to lead to disciplinary action based on pharmacologically insignificant traces of these substances'. The rationale behind this approach is to prevent overly-sensitive testing from inhibiting the proper and appropriate veterinary care of performance horses. This review describes a scientific approach to implement this resolution using local anaesthetics as a model system and compares this approach with others currently in place. For the purpose of this discussion, a 'trace' concentration is defined as a pharmacologically-insignificant concentration. Initially, the target pharmacological effect (e.g. local anaesthesia) was identified, and the dose response relationship was quantified. The 'Highest No Effect Dose' (HNED) was estimated and then administered to horses. Next, the target analyte was identified, synthesized, if necessary, and quantified in blood or urine; the concentrations observed after administration of the HNED are, by definition, true concentrations and hence are pharmacologically insignificant. The key to this approach has been the synthesis of a unique series of authentic equine metabolite standards, which has allowed scientific identification of the concentration at which the pharmacological effect was indistinguishable from control values. Traces found at less than this concentration are, by definition, 'no effect limits', 'no effect traces' (NETs), 'no effect cut-offs', 'no effect limitations on the sensitivity of testing', or 'subtherapeutic residues'. Conversely, this approach will also identify potent medications for which the sensitivity of testing may need to be improved. Within the context of these experiments, the data create an analytical/pharmacological database that should assist industry professionals in interpreting the significance of trace concentrations of these medications or their metabolites in official samples. The most favourable outcome of this research is more medically appropriate use of therapeutic medications in performance horses, yielding substantial benefits to the health and welfare of these horses.

Pharmacokinetic/pharmacodynamic approach to assess irrelevant plasma or urine drug concentrations in postcompetition samples for drug control in the horse

“…Here we present a standardised approach for the treatment of data that has already been published. It is by definition a nonexperimental approach, which differs from the one proposed by Tobin et al (1999) in which a dose-effect relationship is established experimentally, then a dose without effect and finally the corresponding plasma concentration is measured. T h e advantage of the present approach is that it is inexpensive, because it consists of performing a meta-analysis on already existing data.…”

“…glucocorticoids). The approach outlined by Tobin et al (1999) is recommended for these classes of drug. The 2 approaches are compared in Figure 5, together with their domains of application.…”

“…a cut-off plasma or urine concentration corresponding to the HNED. A s quoted by Tobin et al (1999), the limit of this approach is that 'if the drug is administered by different routes of administration, or repeated doses, or a different formulation or with another therapeutic rational, then the analytical pharmacological data base reported (here) may not necessarily be applicable to the specific regulatory circumstances'.…”

Veterinary Medicines and Competition Animals: The Question of Medication Versus Doping Control

“…Detection time is established by racing authorities (or FEI) to give to the practitioner an order of magnitude of the future withholding time. This withholding time is a veterinary decision and the practitioner should perform his own risk analysis to fix the withholding time by adding a safety span to the detection time established by racing organisations < consideration of this approach (see also Houghton (1994); Tobin et al 1998Tobin et al , 1999; (Spencer et al (2008) for reviews).…”

Regulatory control of glycopyrrolate in performance horses using validated UHPLC/MS–MS methods

“…In order to provide the appropriate regulatory control for therapeutic substances that may also have the ability to affect performance, threshold limits must be determined in blood (plasma), urine or both [5][6][7]. Furthermore, it is important to determine the relationship between urine and plasma concentrations after a single intravenous and clinically relevant dose of GLY.…”