Models for assessing the relationship between drug concentration and drug effect in performance horses

The actions of most drugs are dependent upon achieving adequate plasma concentrations. Plasma concentrations are influenced by the degree to which a drug is absorbed, distributed, metabolized and excreted. Pharmacokinetic assessment reflects changes in these variables as a function of time. Pharmacodynamics refers to specific drug effects or mechanisms of drug action. Individual drug pharmacokinetics provides information on which to base a therapeutic dose, route of administration and dosing interval. However, not all drug actions temporally correlate with plasma kinetics. To resolve this discrepancy, pharmacodynamic models of drug action have been developed. In this review several pharmacodynamic models of anti-inflammatory and central nervous system effects are discussed in relationship to individual drug pharmacokinetics in the horse. The use of appropriate statistical models can minimize error and maximize the detection of drug effects over time. Data are presented showing the value of pharmacodynamic models in assessing and predicting the onset, peak and duration of drug action. Penetration of drugs into inflamed tissue or the brain may not temporally correlate with plasma kinetics. Therefore, drug kinetics in tissues or compartments associated with a particular effect may be a better predictor of efficacy than plasma concentrations. Recent studies have shown that exercise can affect drug disposition and influence both pharmacokinetics and pharmacodynamics. In competitive athletes, plasma or urine concentrations of drugs are determined to regulate use. Some jurisdictions are advocating the establishment of specific drug thresholds based upon plasma or urine concentrations. However, drug effects may occur during low or undetectable plasma concentrations. Urine concentrations are often dissociated in time from those in plasma. Therefore, the use of appropriate pharmacodynamic models, and the exercising horse, can complement plasma pharmacokinetics in determining drug efficacy and drug thresholds.